Nonpeptide endothelin antagonists with increased water solubility

ABSTRACT

Novel nonpeptide endothelin I antagonists of Formula                    
     are described wherein R 1  is unsubstituted or substituted cycloalkyl, phenyl, naphthyl or heteroaryl, R 2  is unsubstituted or substituted alkyl, aryl or heteroaryl, R 3  is unsubstituted or substituted alkyl, cycloalkyl, aryl or heteroayl, and R 1  and/or R 2  and/or R 3  are independently substituted by a total of from 1 to 4 substituents which enhance aqueous solubility with the proviso that when R 2  is alkyl and is substituted, the substituent is not oxygen at the α-position of the furanone ring. Further described are methods for the preparation and pharmaceutical compositions of compounds of Formula I, which are useful in treating atherosclerosis, restenosis, Raynaud&#39;s phenomenon, mild or severe congestive heart failure, cerebral ischemia, cerebral infarction, embolic stroke, cerebral vasospasm, glaucoma, subarachnoid hemorrhage, hemorrhagic stroke, diabetes, gastric ulceration and mucosal damage, ischemic bowel disease, Chrohn&#39;s disease, male penile erectile dysfunction, essential or malignant hypertension, pulmonary hypertension, pulmonary hypertension after bypass, cancer, especially malignant hemangioendothelioma or prostate cancer, myocardial infarction or ischemia, acute or chronic renal failure, renal ischemia, radiocontrast-induced nephrotoxcity, endotoxic, septic hemorrhagic shock, angina, preeclampsia, asthma, arrhythmias, benign prostatic hyperplasia, and elevated levels of endothelin.

This application claim a right of provisional application Ser. No.06/015,242 filed on Apr. 10, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to novel antagonists of endothelin usefulas pharmaceutical agents, to methods for their production, topharmaceutical compositions which include these compounds and apharmaceutically acceptable carrier, and to pharmaceutical methods oftreatment. More particularly, the compounds of the present invention areantagonists of endothelin useful in treating elevated levels ofendothelin, angina, arrhythmias, asthma, atherosclerosis, benignprostatic hyperplasia, Buerger's Disease, cardiac arrest, cardiogenicshock, cerebral trauma, Chrohn's Disease, chronic obstructive pulmonarydisease, cryptogenic fibrosing alveolitis, congenital heart disease,congestive heart failure (CHF) (mild), congestive heart failure (CHF)(severe), cerebral ischemia, cerebral infarction, cerebral vasospasm,cirrhosis, diabetes, dilated cardiomyopathy, drowning (anoxia),endotoxic shock, gastric mucosal damage, glaucoma, head injury,hemodialysis, hemorrhagic shock, hypertension (essential), hypertension(malignant), hypertension (pulmonary), hypertension (pulmonary, afterbypass), hypoglycemia, inflammatory arthritides, ischemic bowel disease,ischemic disease, male penis erectile dysfunction, malignanthemangioendothelioma, myocardial infarction, myocardial ischemia,prenatal asphyxia, postoperative cardiac surgery, prostate cancer,preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure(chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoidhemorrhage (acute), surgical operations, status epilepticus, stroke(thromboembolic), stroke (hemorrhagic), Takayasu's arteritis, ulcerativecolitis, uremia after hemodialysis, and uremia before hemodialysis.

Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acidbicyclic peptide that was first isolated from cultured porcine aorticendothelial cells. Endothelin-1, is one of a family of structurallysimilar bicyclic peptides which include: ET-2, ET-3, vasoactiveintestinal contractor (VIC), and the sarafotoxins (SRTXs).

The distribution of the two cloned receptor subtypes, termed ET_(A) andET_(B), have been studied extensively (Arai H., et al., Nature,1990;348:730, Sakurai T., et al., Nature, 1990;348:732). The ET_(A), orvascular smooth muscle receptor, is widely distributed in cardiovasculartissues and in certain regions of the brain (Lin H. Y., et al., Proc.Natl. Acad. Sci., 1991;88:3185). The ET_(B) receptor, originally clonedfrom rat lung, has been found in rat cerebellum and in endothelialcells. The human ET receptor subtypes have been cloned and expressed(Sakamoto A., et al., Biochem. Biophys. Res. Chem., 1991;178:656, HosodaK., et al., FEBS Lett., 1991;287:23). The ET_(A) receptor clearlymediates vasoconstriction and there have been a few reports implicatingthe ET_(B) receptor in the initial vasodilatory response to ET(Takayanagi R., et al., FEBS Lett., 1991;282:103). However, recent datahas shown that the ET_(B) receptor can also mediate vasoconstriction insome tissue beds (Panek R. L., et al., Biochem. Biophys. Res. Commun.,1992;183(2):566).

The involvement of endothelin has been proven in many human diseasestates.

Elevated levels of endothelin have been measured in patients sufferingfrom ischemic heart disease (Yasuda M., et al., Amer. Heart J.,1990;119:801-806) and either stable or unstable angina (Stewart J. T.,et al., Br. Heart J., 1991;66:7-9).

The degree of elevation of plasma ET levels in patients with heartfailure varies from 2-fold to 5-fold (Stewart, et al., Circulation,1992;85:510-517; Lerman, et al., J. Am. Coll. Cardiology,1992;20:849-853). The greatest elevation measured appears to be incongestive heart failure (CHF) patients with marked pulmonaryhypertension. The increased level of circulating ET in human congestiveheart failure patients also correlated with the severity of the diseaseobserved (Rodeheffer, et al., Am. J. Hypertension, 1991:4:9A;Rodeheffer, et al., Mayo Clin. Prod., 1992;67:719-724).

Many studies have indicated increased plasma levels of ET-1 after acutemyocardial infarction (MI) in both animals and humans (Stewart, et al.,J. Am. Coll. Cardiol., 1991:18:38-43; Tomoda, et al., Am. Heart J.,1993;125:667-672; Ray, et al., Br. Heart J., 1992;67:383-386; Tsuji, etal., Life Sci., 1991;48:1745-1749). It has also been reported that theaction of ET-1 may be enhanced under the conditions of ischemia (Liu, etal., Biochem. Biophys. Res. Conmmun., 1989;164:1220-1225).

Several in vivo studies with ET antibodies have been reported in diseasemodels. Left coronary artery ligation and reperfusion to inducemyocardial infarction in the rat heart, caused a 4- to 7-fold increasein endogenous endothelin levels. Administration of ET antibody wasreported to reduce the size of the infarction in a dose-dependent manner(Watanabe T., et al., “Endothelin in Myocardial Infarction,” Nature,(Lond.) 1990;344:114). Thus, ET may be involved in the pathogenesis ofcongestive heart failure and myocardial ischemia (Margulies K. B., etal., “Increased Endothelin in Experimental Heart Failure,” Circulation,1990;82:2226).

Patients with chronic heart failure were treated with the ET antagonistBosentan, which was found to improve cardiac performance, concludingthat ET is involved in the regulation of vascular tone and thatinhibition of its effects may be beneficial in chronic heart failure(Kiowski W., et al., Lancet, 1995;346:732-36, also J. Am. Coll.Cardiol., 1995; special edition 296A:779-1).

Infusion of an endothelin antibody 1 hour prior to and 1 hour after a 60minute period of renal ischaemia resulted in changes in renal functionversus control. In addition, an increase in glomerularplatelet-activating factor was attributed to endothelin (Lopez-Farre A.,et al., J. Physiology, 1991;444: 513-522). In patients with chronicrenal failure as well as in patients on regular hemodialysis treatmentmean plasma endothelin levels were significantly increased (StockenhuberF., et al., Clin. Sci. (Lond.), 1992;82:255-258).

Studies by Kon and colleagues using anti-ET antibodies in an ischemickidney model, to deactivate endogenous ET, indicated the peptide'sinvolvement in acute renal ischemic injury (Kon V., et al., “GlomerularActions of Endothelin In Vivo,” J. Clin. Invest., 1989;83:1762).

Other investigators have reported that infusion of ET-specificantibodies into spontaneously hypertensive rats (SHR) decreased meanarterial pressure (MAP), and increased glomerular filtration rate andrenal blood flow. In the control study with normotensive Wistar-Kyotorats (WKY) there were no significant changes in these parameters (OhnoA., Effects of Endothelin-Specific Antibodies and Endothelin inSpontaneously Hypertensive Rats,” J. Tokyo Women's Med. Coll.,1991;61:951).

Other studies have demonstrated the usefulness of ET antagonists inmaintaining beneficial parameters of renal performance followingischemia-induced injuries (Mino, et al., Eur. J. Pharmacol.,1992;221:77-83; Benigni, et al., Kidney Int, 1993;44:440-444).

ET_(A) receptor mRNA has been detected in 82% of human meningiomas (J.Clin. Invest., 1995;66:2017-2025

Plasma endothelin-1 levels were dramatically increased in a cancerpatient with malignant hemangioendothelioma (Nakagawa K., et al., NipponHifuka Gakkai Zasshi, 1990;100:1453-1456).

Exogenous endothelin-1 is also a prostate cancer mitrogen in vitro.Endothelin levels are significantly elevated in men with metastaticprostate cancer. Every human prostate cancer cell line tested by Nelsonet al., (Nature Medicine, 1995; Vol 1(9):944) produced ET-1 mRNA andsecreted immunoreactive endothelin.

An ET antagonist, PD 155080 was found to mediate prostate smooth musclefunction in vivo, which demonstrated that endothelin antagonists may beuseful in the treatment of benign prostatic hyperplasia (Chleko I., etal., Annual Meeting of the American Urological Assn, Orlando, 1996).

The ET receptor antagonist BQ-123 has been shown to block ET-1 inducedbronchoconstriction and tracheal smooth muscle contraction in allergicsheep providing evidence for expected efficacy in bronchopulmonarydiseases such as asthma (Noguchi, et al., Am. Rev. Respir. Dis.,1992;145(4 Part 2):A858).

Circulating endothelin levels are elevated in women with preeclampsiaand correlate closely with serum uric acid levels and measures of renaldysfunction. These observations indicate a role for ET in renalconstriction in preeclampsia (Clark B. A., et al., Am. J. Obstet.Gynecol., 1992;166:962-968).

Plasma immunoreactive endothelin-1 concentrations are elevated inpatients with sepsis and correlate with the degree of illness anddepression of cardiac output (Pittett J., et al., Ann. Surg.,1991;213(3):262).

In addition, the ET-1 antagonist BQ-123 has been evaluated in a mousemodel of endotoxic shock. This ET_(A) antagonist significantly increasedthe survival rate in this model (Toshiaki M., et al., 20.12.90. EP 0 436189 A1).

Endothelin is a potent agonist in the liver eliciting both sustainedvasoconstriction of the hepatic vasculature and a significant increasein hepatic glucose output (Gandhi C. B., et al., Jornal of BiologicalChemistry, 1990;265(29):17432). In addition increased levels of plasmaET-1 have been observed in microalbuminuric insulin-dependent diabetesmellitus patients indicating a role for ET in endocrine disorders suchas diabetes (Collier A., et al., Diabetes Care, 1992;15(8):1038).

Infusion of ET-1 produced a sustained, reversible, and salt-dependenthypertension when infused into normal, conscious rats (Mortensen, etal., Hypertensrion, 1990;15:720-723; Mortensen, et al., FASEB J.,1991;5: A1105).

ET_(A) antagonist receptor blockade has been found to produce anantihypertensive effect in normal to low renin models of hypertensionwith a time course similar to the inhibition of ET-1 pressor responses(Basil M. K., et al., J. Hypertension, 1992;10(Suppl. 4):S49). Theendothelins have been shown to be arrhythmogenic, and to have positivechronotropic and inotropic effects, thus ET receptor blockade would beexpected to be useful in arrhythmia and other cardiovascular disorders(Han S.-P., et al., Life Sci., 1990;46:767).

Recently, an ET_(A) selective antagonist demonstrated an oralantihypertensive effect (Stein P. D., et al., “The Discovery ofSulfonamide Endothelin Antagonists and the Development of the OrallyActive ET_(A) Antagonist5-(Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide,”J. Med. Chem., 1994;37: 329-331).

Plasma ET levels are elevated in patients with pulmonary hypertension(Yoshibayashi M., et al., Circulation, 1991;84:2280-2285). Increasedexpression has been measured indicating local production in the lung.Pulmonary hypertension is associated with the increased expression ofendothelin-1 in vascular endothelial cells, suggesting that the localproduction of endothelin-1 may contribute to vascular abnormalitiesassociated with pulmonary hypertension (Giaid A., et al., N. Engl. J.Med., 1993;328:1732-9). In pulmonary hypertension, ET-1 is the mostpotent constrictor of airway smooth muscle thus far described in vitro(Pons, et al., J. Pharmacol., 1991;102: 791-796). This response has beenblocked by ET_(A)-receptor antagonists (Abraham, et al., J. Appl.Physiol., 1993;74(5);2537-2542). Endothelin antagonists that block theproduction of endothelin and hence lower levels of endothelin have shownefficacy in several animal models of pulmonary hypertension. Pulmonaryhypoxia increases ET-1 expression in the lung (J. Surg. Res.,1994;57:280-283). For example, BQ-123, Bosentan, and PD 156707 provideprotection in a rat hypoxia model of hypertension by lowering theincrease in pulmonary vascular resistance and pulmonary arterialpressure (Eddahibi S., et al., Am. J. Physiol., 1995;268: H828-835;Bonvallet S. T., et al., Am. Rev. Resp.Dis., 1993;147: A493; IBCInternational Conference, R. Bialecki, Feb. 5, 1996, Coronado, Calif.).ET_(A)-receptor antagonists have been found to prevent and reversechronic hypoxia-induced pulmonary hypertension in rat (DiCarlo, et al.,Am. J. Physiol., 1995;269: L690-L697; Chen, et al., J. Appl. Physiol.,1995;79(6):2122-2131).

There is evidence that suggests the extent of increase in plasma ET-1levels in patients with pulmonary hypertension may reflect theabnormalities of pulmonary circulation. It has been demonstrated thatthe pulmonary artery endothelial cells are injured in patients withcongenital heart disease (Ishikawa S., et al., J. Thorac. Cardiovasc.Surg., 1995;110:271-3) Further, in cardiopulmonary bypass operations onpatients with congenital heart disease, an immediate postoperativeincrease in circulating endothelin was observed which may predispose thepatient to pulmonary vascular lability and crises in the postoperativeperiod (Komai H., et al., J. Thora. Cardiovasc. Surg., 1993;106:473-8).

The widespread localization of the endothelins and their receptors inthe central nervous system and cerebrovascular circulation has beendescribed (Nikolov R. K., et al., Drugs of Today, 1992;28(5): 303-310).Intracerebroventricular administration of ET-1 in rats has been shown toevoke several behavioral effects. The potent vasoconstrictor action ofETs on isolated cerebral arterioles suggests the importance of thesepeptides in the regulation of cerebrovascular tone. These factorsstrongly suggest a role for the ETs in neurological disorders.

The volume of ischemic damage in the cerebral hemisphere of catsfollowing middle cerebral artery occlusion was significantly reducedafter the IV administration of PD 156707 (Patel, et al., J. Cardiovasc.Pharmacol., 1995;26(Suppl. 3):S412-S415). Reduction of ischemic braininjury in rats was also demonstrated following oral administration ofthe endothelin antagonist SB 217242 (Barone, et al., J. Cardiovasc.Pharmacol., 1995;26(Suppl. 3): S404-S407).

Several studies have shown that endothelin levels are elevated in acuteand chronic renal failure (Torralbo A., et al., Am. J. Kid. Dis.,1995;25(16):918-923). Data in models of acute renal failure indicatethat endothelin plays an important role. An endothelin receptorantagonist Bosentan that can block endothelin production and therebylower levels has been reported to be effective in models of acute renalischemia (Clozel M., et al., Nature, 1995;365:759). In dogs, theendothelin receptor antagonist SB 2090670 can attenuate ischemia-inducedreductions in glomerular filtration rate and increases in fractionalsodium excretion (Brooks D. P., et al., J. Pharmacol. Exp. Ther., 1995).In addition, several antagonists have been shown to blockradiocontrast-induced nephrotoxicity (Oldroyd S., et al., Radiology,1995;196:661-665).

TAK-044 has shown protective effects in a model of acute renal failurein rats (Life Sci., 1994;55(4):301-310).

The ET_(A) antagonist BQ-123 has been shown to prevent early cerebralvasospasm following subarachnoid hemorrhage (SAH) (Clozel M. andWatanabe H., Life Sci., 1993;52:825-834; Lee K. S., et al., CerebralVasospasm, 1993:217; and Neurosugery, 1994;34:108). FR 139317significantly inhibited the vasoconstriction of the basilar artery after7 days in a canine two-hemorrhage model of SAH (Nirei H., et al., LifeSci., 1993;52:1869). BQ-485 also significantly inhibited thevasoconstriction of the basilar artery after 7 days in a caninetwo-hemorrhage model of SAH (Yano, et al., Biochem. Biophys. Res.Commun., 1993; 195:969). Ro 46-2005 (Clozel M., et al., Nature,1993;365:759) has been shown to prevent early cerebral vasospasmfollowing SAH in the rat with no significant effect on systemic arterialblood pressure. Treatment with Ro 47-0203=Bosentan (Clozel, et al.,Circulation, 1993;88(4) part 2:0907) to rabbits with SAH had a 36±7%reduction of basilar artery cross-sectional area compared to shamrabbits. All of these studies show in vivo efficacy of endothelinantagonists in cerebral vasospasm resulting from SAH.

Circulating and tissue endothelin immunoreactivity is increased morethan 2-fold in patients with advanced atherosclerosis (Lerman A., etal., New England J.T Med., 1991;325:997-1001). Increased endothelinimmunoreactivity has also been associated with Buerger's disease (KannoK., et al., J. Amer. Med. Assoc., 1990;264:2868) and Raynaud'sphenomenon (Zamora M. R., et al., Lancet, 1990;336:1144-1147).

An increase of circulating endothelin levels was observed in patientsthat underwent percutaneous transluminal coronary angioplasty (PTCA)(Tahara A., et al., Metab. Clin. Exp., 1991;40:1235-1237).

In an experiment to minimize restenosis following carotid artery balloonangioplasty in rats, the ET receptor antagonist SB 209670 was found toameliorate neointima formation (Douglas, et al., Circulation Res.,1994;75:190-197).

Local intra-arterial administration of endothelin has been shown toinduce small intestinal mucosal damage in rats in a dose-dependentmanner (Mirua S., et al., Digestion, 1991;48:163-172; Masuda E., et al.,Am. J. Physiol., 1992;262: G785-G790). Elevated endothelin levels havebeen observed in patients suffering from Crohn's disease and ulcerativecolitis (Murch S. H., et al., Lancet, 1992;339:381-384).

The ET receptor antagonist bosentan was found to be an antagonist towardthe ET-1-induced changes in gastric mucosal hemodynamics as well as onET-1-induced gastric ulceration (Lazaratos, et al., Pharmacol. Lett.,1995;56(9):195-200).

Graefe's Arch. Clin. Exp. Ophthalmol, 1995;233(8):484-488 provides datato support the hypothesis that vascular dysfunction may be involved inthe pathogenesis of optic nerve damage in normal-tension glaucoma.

Eur. J. Pharmacol., 1996;307(1):69-74 teaches a role for endothelins inpenile erection.

Release of eicosanoids and endothelin in an experimental model of adultrespiratory distress syndrome (ARDS) is covered in Agents ActionsSuppl., Prostaglandins Cardiovasc. Syst., 1992;37:41-6.

Am. Rev. Respir. Dis., 1993;148:1169-1173 teaches venous ET-1concentrations are massively increased in ARDS as a result of bothincreased formation and decreased clearance.

Chest, 1993;104:476-80 shows plasma ET-1 levels also positivelycorrelate with right atrial pressure, systolic pulmonary arterialpressure, mean pulmonary arterial pressure, and resistance ratio(pulmonary vascular resistance/systemic vascular resistance) in ARDS.

In chronic obstructive pulmonary disease (COPD) and Cor Pulmonaleassociated with pulmonary hypertension patients excrete higher amountsof ET-1 compared to healthy subjects. Urinary ET-1 levels are furtherincreased during acute exacerbation of the disease.

ET-1 levels in broncho alveolar lavage fluid from patients with COPDhave been reported. ET-1 is involved in pulmonary endothelium damagecaused by hypoxia in COPD patients. Pulmonary artery hypertension is theprimary cardiovascular complication in COPD. (See Sofia, et al.,Respiration, 1994:263-268(61); “Increased 24-Hour endothelin-1 urinaryexcretion in patients with chronic obstructive pulmonary disease” andMatthay, et al., Medical Clinics of North America, 1990:571-618(74);“Cardiovascular pulmonary interaction in chronic obstructive pulmonarydisease with special reference to the pathogenesis and management of CorPulmonale.”

ET-1 expression is increased in the lung vasculature of patients withpulmonary hypertension contributes to the medial hyperplasia and atrialfibrosis of cryptogenic fibrosing alveolitis. See Giaid, et al., TheLancet, 1993:1550-1554(341) Expression of endothelin-1 in lungs ofpatients with cryptogenic fibrosing alveolitis.

In summary, some of the conditions in which ET antagonists may be usefulin treatment are as follows: angina, arrhythmias, asthma,atherosclerosis, benign prostatic hyperplasia, Buerger's Disease,cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease,chronic obstructive pulmonary disease, cryptogenic fibrosing alveolitis,congenital heart disease, congestive heart failure (CHF) (mild),congestive heart failure (CHF) (severe), cerebral ischemia, cerebralinfarction, cerebral vasospasm, cirrhosis, diabetes, dilatedcardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosaldamage, glaucoma, head injury, hemodialysis, hemorrhagic shock,hypertension (essential), hypertension (malignant), hypertension(pulmonary), hypertension (pulmonary, after bypass), hypoglycemia,inflammatory arthritides, ischemic bowel disease, ischemic disease, malepenile erectile dysfunction, malignant hemangioendothelioma, myocardialinfarction, myocardial ischemia, prenatal asphyxia, postoperativecardiac surgery, prostate cancer, preeclampsia, Raynaud's Phenomenon,renal failure (acute), renal failure (chronic), renal ischemia,restenosis, sepsis syndrome, subarachnoid hemorrhage (acute), surgicaloperations, status epilepticus, stroke (thromboembolic), stroke(hemorrhagic), Takayasu's arteritis, ulcerative colitis, uremia afterhemodialysis, and uremia before hemodialysis.

TABLE I Plasma Concentrations of ET-1 in Humans ET Plasma Levels NormalReported Condition Control (pg/mL) Atherosclerosis 1.4 3.2 pmol/LSurgical operation 1.5 7.3 Buerger's disease 1.6 4.8 Takayasu'sarteritis 1.6 5.3 Cardiogenic shock 0.3 3.7 Congestive heart failure 9.720.4 (CHF) Mild CHF 7.1 11.1 Severe CHF 7.1 13.8 Dilated cardiomyopathy1.6 7.1 Preeclampsia 10.4 pmol/L 22.6 pmol/L Pulmonary hypertension 1.453.5 Acute myocardial infarction 1.5 3.3 (several reports) 6.0 11.0 0.764.95 0.50 3.8 Subarachnoid hemorrhage 0.4 2.2 Crohn's Disease 0-24fmol/mg  4-64 fmol/mg Ulcerative colitis 0-24 fmol/mg 20-50 fmol/mg Coldpressor test 1.2 8.4 Raynaud's phenomenon 1.7 5.3 Raynaud's/hand cooling2.8 5.0 Hemodialysis <7 10.9 (several reports) 1.88 4.59 Chronic renalfailure 1.88 10.1 Acute renal failure 1.5 10.4 Uremia beforehemodialysis 0.96 1.49 Uremia after hemodialysis 0.96 2.19 Essentialhypertension 18.5 33.9 Sepsis syndrome 6.1 19.9 Postoperative cardiac6.1 11.9 Inflammatory arthritides 1.5 4.2 Malignant hemangioendothelioma4.3 16.2 (after removal)

Allen C. F. H., Frame G. F., Can. J. Research, 1932; 6:605 teaches thecondensation of methyl and ethylα-phenyl-β-(para-substituted)benzoylpropionates with benzaldehyde andpiperonal in the presence of sodium methylate, followed byacidification, produces cyclic compounds.

Allen C. F. H., Frame G. F., Normington J. B., Wilson C. V., Can. J.Research, 1933;8:137 teaches the condensation of benzaldehyde withmethyl and ethyl α-aryl-β-benzoylpropionates in the presence of sodiummethylate, followed by acidification, to give unsaturated ketonic acids.

Allen, C. F., Normington, J. B., Wilson, C. V., Can. Research, 1934;11:382 recites a number of highly substituted acrylic acids or theirlactols.

Allen, C. F. H., Davis, T. J., Stewart, D. W., VanAllan, J. A., Can. J.Chem., 1956;34:926 shows that α aryl-β-aroylpropionic acids exist in anopen-chain configuration while the condensation products of these latteracids with aromatic aldehydes are lactols, refuting his previous articleCan. J. Research, 1933;8:137.

Copending U.S. Pat. No. 5,691,373 covers nonpeptide endothelinantagonists of Formula II

or a tautomeric open chain ketoacid form thereof or a pharmaceuticallyacceptable salt thereof wherein

R₁ is cycloalkyl substituted or unsubstituted of from 3 to 12 carbonatoms,

phenyl substituted with from 1 to 5 substituents,

naphthyl unsubstituted or substituted with from 1 to 5 substituents, or

heteroaryl unsubstituted or substituted with from 1 to 5 substituents;

R₂ is alkyl substituted or unsubstituted straight, or branched of from 1to 12 carbon atoms,

cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms,

aryl which is unsubstituted or substituted with from 1 to 5substituents,

heteroaryl which is unsubstituted or substituted with from 1 to 3substituents;

R₃ is alkyl substituted or unsubstituted straight, or branched, of from1 to 12 carbon atoms,

cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms,

aryl which is unsubstituted or substituted with from 1 to 5substituents,

heteroaryl which is unsubstituted or substituted with from 1 to 3substituents;

R₄ is hydroxy or OR₅,

SR₅, wherein R₅ is alkyl or substituted alkyl of from 1 to 7 carbonatoms, or

(CH₂)_(n)OR₅ wherein n is an integer of from 1 to 3;

X is O or S;

with the proviso that when R₁ is monosubstituted phenyl and thesubstituent is p-methoxy, R₃ is not unsubstituted phenyl,monosubstituted phenyl, or mesityl and with the further proviso when R₂is alkyl substituted, the substituent is not oxygen at the α-position tothe furanone ring.

This patent is hereby incorporated by reference.

Compounds of Formula

IA

wherein: R₁ R₂ R₃ phenyl phenyl phenyl phenyl phenyl p-chloro- phenylphenyl phenyl p-bromo- phenyl piperonyl

phenyl p-chloro- phenyl phenyl o-chlorophenyl phenyl phenyl phenylp-phenyl- phenyl anisyl (p-methoxyphenyl) phenyl phenyl anisyl α-furylphenyl phenyl piperonyl p-chloro- phenyl anisyl o-chlorophenyl phenylanisyl o-methoxy- phenyl phenyl phenyl phenyl mesityl phenyl phenylp-methyl- phenyl phenyl o-chlorophenyl p-chloro- phenyl phenyl phenylp-methoxy- phenyl anisyl o-methylphenyl phenyl phenyl piperonyl p-bromo-phenyl phenyl piperonyl p-methoxy- phenyl

are all known. However, the methods of using 2(5H)-furanone,3-(1,3-benzodioxol-5-yl)-5-(4-chlorophenyl)-5-hydroxy-4-(phenylmethyl)-and a pharmaceutical composition containing it are taught in the aboveco-pending application.

SUMMARY OF THE INVENTION

The instant invention is a compound of Formula I

or a tautomeric open chain keto-acid form thereof or a pharmaceuticallyacceptable salt thereof wherein

R₁ is cycloalkyl of from 3 to 12 carbon atoms substituted orunsubstituted,

phenyl substituted with from 1 to 5 substituents,

naphthyl unsubstituted or substituted with from 1 to 5 substituents, or

heteroaryl unsubstituted or substituted with from 1 to 5 substituents;

R₂ is straight or branched alkyl of from 1 to 12 carbon atomssubstituted or unsubstituted,

cycloalkyl of from 3 to 12 carbon atoms substituted or unsubstituted,

aryl unsubstituted or substituted with from 1 to 5 substituents, or

heteroaryl unsubstituted or substituted with from 1 to 3 substituents;

R₃ is straight or branched alkyl of from 1 to 12 carbon atomssubstituted or unsubstituted,

cycloalkyl of from 3 to 12 carbon atoms substituted or unsubstituted,

aryl which is unsubstituted or substituted with from 1 to 5substituents, or

heteroaryl unsubstituted or substituted with from 1 to 3 substituents;

at least one of R₁ or R₂ or R₃ is substituted by a substituent whichenhances aqueous solubility. Up to four aqueous solubility groups may beattached independently to R₁ and/or R₂ and/or R₃. These aqueoussolubility enhancing groups consist of secondary aminos, tertiary aminos(where the tertiary amino may be a cyclic structure and further maycontain additional hetero atoms) or a sulfonic acid moiety; with theproviso that when R₂ is alkyl and is substituted, the substituent is notoxygen at the α-position to the furanone ring.

Preferred compounds of the instant invention are those of Formula Iwherein

R₁ is phenyl substituted with from 1 to 5 substituents,

R₂ is straight or branched alkyl of from 1 to 9 carbon atoms substitutedwith from 1 to 7 substitutents,

R₃ is aryl substituted or unsubstituted;

at least one of Groups R₁ or R₂ or R₃ is substituted by a substituentwhich enhances aqueous solubility. Up to four aqueous solubility groupsmay be attached independently to R₁ and/or R₂ and/or R₃. These aqueoussolubility enhancing groups consist of secondary aminos, tertiary aminos(where the tertiary amino may be a cyclic structure and further maycontain additional hetero atoms) or a sulfonic acid moiety;

with the proviso when R₂ is alkyl and is substituted, the substituent isnot oxygen at the α-position to the furanone ring. In those cases whereR₂ is a substituted aryl or heteroaryl group, the aqueous solubilizinggroup would be attached to the aryl or heteroaryl.

More preferred compounds of the instant invention are those of Formula Iwherein

R₁ is phenyl substituted with from 1 to 5 substituents;

R₂ is straight or branched alkyl of from 1 to 7 carbons substituted withfrom 1 to 7 substituents;

R₃ is aryl substituted or unsubstituted;

At least one of the substituents on R₁ and/or R₂ and/or R₃ have asubstituent selected from:

—O—(Ch₂)₁₋₆N(R₄)₂,

—NH—(Ch₂)₁₋₆N(R₄)₂ wherein R₄ is alkyl of from 1 to 6 carbons,

 wherein R⁵ is hydrogen or lower alkyl,

—O—(Ch₂)₁₋₆—SO₃H,

—NH—(Ch₂)₁₋₆—SO₃H,

 wherein R⁶ is alkyl of from 1 to 6 carbons,

—(CH₂)₀₋₆N(alkyl)₂,

with the proviso that when R₂ is alkyl and is substituted, thesubstituent is not oxygen at the α-position to the furanone ring.

More preferred compounds of the instant invention are those of Formula Iwherein

R₁ is 4-piperonyl,

3,5-dimethoxyphenyl, or

3-methoxy-4,5-methylenedioxyphenyl;

R₂ is 4-(3-dimethylaminopropoxy)benzyl,

3-(3-dimethylaminopropoxy)benzyl,

5-(3-dimethylaminopropoxy)-3,4-dimethoxybenzyl,

5-(2-morpholin-4-yl-ethoxy)-3,4-dimethoxybenzyl,

5-(3-morpholin-4-yl-propoxy)-3,4-dimethoxybenzyl,5-(3-(4-methyl-piperazin-1-yl)propoxy)-3,4-dimethoxybenzyl,

5-(2-(4-methyl-piperazin-1-yl)ethoxy)-3,4-dimethoxybenzyl,

4-(2-(4-methyl-piperazin-l-yl)ethoxy)benzyl,

3-(2-(4-methyl-piperazin-l-yl)ethoxy)benzyl,

4-(3-(4-methyl-piperazin-l-yl)propoxy)benzyl,

3-(3-(4-methyl-piperazin-l-yl)propoxy)benzyl,

4-(2-morpholin-4-yl-ethoxy)benzyl,

3-(2-morpholin-4-yl-ethoxy)benzyl,

4-(2-pyrrolidinyl-ethoxy)benzyl,

3-(2-pyrrolidinyl-ethoxy)benzyl,

4-(3-pyrrolidinyl-propoxy)benzyl,

3-(3-pyrrolidinyl-propoxy)benzyl,

5-(3-pyrrolidinyl-propoxy)-3,4-dimethoxybenzyl,

5-(2-pyrrolidinyl-ethoxy)-3,4-dimethoxybenzyl,

3,4,5-trimethoxybenzyl, benzyl;

R₃ is 3,4-dimethoxyphenyl,

3-methyl-4-methoxyphenyl,

2,4-dimethoxyphenyl,

4-methoxyphenyl,

4-(3-dimethylaminopropoxy)phenyl, or

4-(2-morpholin-4-ylethoxy)phenyl;

R₄ is hydroxy; and

at least one R₁ and/or R₂ and/or R₃ is substituted by a substituentwhich enhances aqueous solubility and up to four aqueous solubilitygroups may be attached independently to R₁ and/or R₂ and/or R₃. Theseaqueous solubility enhancing groups consist of secondary aminos,tertiary aminos (where the tertiary amino may be a cyclic structure andfurther may contain additional hetero atoms) or a sulfonic acid moiety.

Still more preferred compounds of the instant invention are selectedfrom:

3-Benzo[1,3]dioxol-5-yl-4-[4-(3-dimethylamino-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

2-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-N-(2-morpholin-4-yl-ethyl)-acetamide,

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-4-[3-(2-dimethylamino-ethoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-4-[3-(3-dimethylamino-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-[3-(2-morpholin-4-yl-ethoxy)-benzyl]-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-[4-(3-dimethylamino-propoxy)-phenyl]-5-hydroxy-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-4-[3-(3-dimethylamino-propoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-4-[3-methoxy-4,5-bis-(2-morpholin-4-yl-ethoxy)-benzyl]-5-(4-methoxy-phenyl)-5H-furan-2-one,

4-(3-Dimethylaminomethyl-benzyl)-5-hydroxy-3-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-(3-Dimethylaminomethyl-benzyl)-2-(7-methoxy-benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoicacid monosodium salt,

3-Benzo[1,3]dioxol-5-yl-4-[3-(2-dimethylamino-ethoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5-(3-morpholin-4-yl-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-4-{3,4-dimethyoxy-5-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-[2-(3-dimethylamino-propoxy)-4-methoxy-phenyl]-5-hydroxy-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one,

3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-propane-1-sulfonicacid,

3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-butane-1-sulfonicacid,

3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-ethane-1-sulfonicacid,

3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-pentane-1-sulfonicacid,

3-Benzo[1,3]dioxol-5-yl-4-(3-dimethylaminomethyl-benzyl)-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3-methylamino-benzyl)-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-{3-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-5H-furan-2-one,

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-[3-(3-morpholin-4-yl-propoxy)-benzyl]-5H-furan-2-one,

3-[3-(2-Dimethylamino-ethoxy)-5-methoxy-phenyl]-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one,

3-(3,5-Dimethoxy-phenyl)-4-[3-(2-dimethylamino-ethoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,and

4-{3,4-Dimethoxy-5-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-3-(3,5-dimethoxy-phenyl)-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one.

Elevated levels of endothelin have been shown to be involved in a numberof pathophysiological states including angina, arrhythmias, asthma,atherosclerosis, benign prostatic hyperplasia, Buerger's Disease,cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease,congenital heart disease, congestive heart failure (CHF) (mild),congestive heart failure (CHF) (severe), cerebral ischemia, cerebralinfarction, cerebral vasospasm, cirrhosis, diabetes, dilatedcardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosaldamage, head injury, hemodialysis, hemorrhagic shock, hypertension(essential), hypertension (malignant), hypertension (pulmonary),hypertension (pulmonary, after bypass), hypoglycemia, inflammatoryarthritides, ischemic bowel disease, ischemic disease, malignanthemangioendothelioma, myocardial infarction, myocardial ischemia,prenatal asphyxia, postoperative cardiac surgery, prostate cancer,preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure(chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoidhemorrhage (acute), surgical operations, status epilepticus, stroke(thromboembolic), stroke (hemorrhagic), Takayasu's arteritis, ulcerativecolitis, uremia after hemodialysis, and uremia before hemodialysis. Asantagonists of endothelin, the compounds of Formula I are useful intheir treatment.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering a therapeutically effective amount of acompound of Formula I in unit dosage form in the treatment methodsmentioned above.

Finally, the present invention is directed to methods for production ofa compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The solubilizing groups are selected from secondary or tertiary aminogroups and sulfonic acids. The secondary amino groups are substituted bystraight or branched chain alkyl, aryl, and heteroaryl, each of whichcan be either unsubstituted or substituted by alkoxy, hydroxy, alkyl,carboxy, carboethoxy, carbomethoxy, amino, monosubstituted amino,disubstituted amino, and nitro. The tertiary amino group hassubstituents independently selected from straight or branched alkylwhich is unsubstituted or substituted by alkoxy, hydroxy, alkyl,carboxy, carboethoxy, carbomethoxy, amino, monosubstituted amino,disubstituted amino, and nitro. Other substituents are aryl andheteroaryl groups, each of which can be substituted or unsubstituted.

The substituents on the tertiary amino group can form a ring with thenitrogen into which they are attached, and may optionally containadditional heteroatoms such as N—R, O or S, such groups as morpholinyl,piperazinyl, and pyrrolidinyl. Preferred are the morpholinyl,piperazinyl, and 4-methyl piperazinyl solubilizing groups.

In the compounds of Formula I, the term “alkyl” means a straight orbranched hydrocarbon radical having from 1 to 12 carbon atoms unlessotherwise specified and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, allyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl. Thealkyl group is unsubstituted or substituted by from 1 to 3 substituentsselected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy,thiol, nitro, halogen, amino, mono and disubstituted amino, formyl,cycloalkyl, carboxyl, nitrile,

aryl, or heteroaryl wherein alkyl, aryl, and heteroaryl are defined asherein.

The term “cycloalkyl” means a saturated hydrocarbon ring which containsfrom 3 to 12 carbon atoms unless otherwise specified, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andadamantyl. The cycloalkyl ring may be unsubstituted or substituted byfrom 1 to 3 substituents selected from alkyl, cycloalkyl, cycloalkoxy,alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro,halogen, amino, mono and disubstituted amino, formyl, carboxyl, nitrile,alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl,

aryl, or heteroaryl wherein alkyl, aryl, and heteroaryl are defined asherein.

The terms “alkoxy” and “thioalkoxy” are O-alkyl or S-alkyl as definedabove for alkyl.

Two alkoxy or thioalkoxy groups can be taken together to form a cyclicgroup such as

where X and Y are independently either O or S and n=1, 2, 3, or 4.

The term “aryl” means an aromatic radical which is a phenyl group, abenzyl group, a naphthyl group, a biphenyl group, a pyrenyl group, ananthracenyl group, or a fluorenyl group and the like, unsubstituted orsubstituted by 1 to 5 substituents selected from alkyl as defined above,alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol,nitro, halogen, amino, mono and disubstituted amino, formyl, carboxy,nitrile, arylsulfoxyl, alkylsulfoxyl, arylsulfonyl, alkylsulfonyl,

or heteroaryl wherein alkyl, aryl, and heteroaryl are defined as above.

The term “heteroaryl” means a heteroaromatic radical which is 2- or3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl,3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-,4-, 5-, 6-, or 7-benzo[b]thienyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl,2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl, unsubstituted or substituted by 1 to 3 substituentsselected from alkyl as defined above, aryl as defined above, alkoxy asdefined above, thioalkoxy as defined above, hydroxy, thiol, nitro,halogen, formyl, amino, mono and disubstituted amino, carboxyl,

wherein alkyl is as defined above or phenyl.

“Halogen” is fluorine, chlorine, bromine or iodine.

Secondary amino is defined by a nitrogen with two groups attached,R_(a)—NH—R_(b).

Tetiary amino is defined by a nitrogen with three groups attached,R_(a)—NR_(b)R_(c).

The secondary and tertiary amino groups can occur as the immediatesubstitution or may be a substituent on any of the above defined groups.

Some of the compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, isethionic, and the like.Also contemplated are salts of amino acids such as arginate and the likeand gluconate, galacturonate (see, for example, Berge, S. M., et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Science,1977;66:1-19).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge, S. M., et al., “Pharmaceutical Salts,” Journalof Pharmaceutical Science, 1977;66:1-19).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof. In addition,some of the cyclic lactones of Formula I may exist in a tautomeric openchain keto-acid form, Formula II below, depending on the substitutionpattern present at R₁, R₂, and R₃, or pH.

In such cases, the rate of equilibration may vary and activity may thusreside with either tautomer.

The compounds of Formula I are valuable antagonists of endothelin. Thetests employed indicate that compounds of the invention possessendothelin antagonist activity. Thus, the compounds were tested fortheir ability to inhibit [¹²⁵I]-ET-1([¹²⁵I]-Endothelin-1) binding in areceptor assay. Selected compounds were also tested for antagonistactivity by inhibition of ET-1 stimulated arachidonic acid release andET-1 stimulated vasoconstriction.

The following radioligand binding assays were used (Reynolds E. E.,Keiser J. A., Haleen S. J., Walker D. M., Davis L. S., Olszewski B.,Taylor D. G., Hwang O., Welch K. M., Flynn M. A., Thompson D. M., etal., J. Pharmacol. Exp. Ther., 1995;273:1410-1417).

The following cultured cells were used in binding experiments: CHO-K1cells expressing recombinant human ET_(B)R (HERBA B), or Ltk-cellsexpressing human ET_(A)R (HERBA A). Each of these cell types expressed ahomogeneous population of the designated ET receptor subtype, whichdisplayed canonical ET_(A)R or ET_(B)R pharmacology. Membranes wereprepared from cultured cells by lysing cells in cold lysis buffer (5 mMHEPES, 2 mM EDTA, pH 7.4) and homogenizing with a Dounce “A”homogenizer. All of the homogenates were centrifuged at 30,000× g for 20minutes at 4° C. Membrane pellets were resuspended in cold buffercontaining 20 mM Tris, 2 EM EDTA, 200 μM Pefablock, 10 μMphosphoramidon, 10 μM leupeptin, and 1 μM pepstatin (pH 7.4) and frozenat −80° C. until use. Radioligand and competing ligands were prepared inbinding buffer containing 20 mM Tris, 2 mM EDTA, and 0.1% BSA.

Competition binding assays were initiated by combining membranes,[¹²⁵1]-ET-1 (40 pM) and competing ligand in a final volume of 250 μL andincubating for 2 hours at 37° C. The assay was terminated by filtrationover Whatman GF/B filters that were presoaked with 50 mM Tris, pH 7.4,containing 0.2% BSA and 100 μM bacitracin. Nonspecific binding wasdefined as total binding minus nonspecific binding. Specific binding wasanalyzed by nonlinear least squared curve fitting (InPlot, GraphPadSoftware, San Diego, Calif.), and the estimated IC₅₀ value was used tocalculate K_(i) according to the method of Cheng and Prusoff (1973).

The following testing procedures were used (Doherty A. M., et al.,“Design of C-Terminal Peptide Antagonists of Endothelin:Structure-Activity Relationships of ET-1 [16-21, D-His¹⁶ ],” Bioorganicand Medicinal Chemistry Letters, 1993;3:497-502).

Antagonist activity is measured by the ability of added compounds toreduce endothelin-stimulated arachidonic acid release in culturedvascular smooth muscle cells as arachidonic acid release (AAR).[³H]Arachidonic Acid Loading Media (LM) is DME/F12+0.5% FCS×0.25 mCi/mL[³H]arachidonic acid (Amersham). Confluent monolayers of cultured rabbitrenal artery vascular smooth muscle cells were incubated in 0.5 mL ofthe LM over 18 hours, at 37° C., in 5% CO₂. The LM was aspirated, andthe cells were washed once with the assay buffer (Hank's BSS+10 mMHEPES+fatty acid-free BSA [1 mg/mL], and incubated for 5 minutes with 1mL of the prewarmed assay buffer. This solution was aspirated, followedby an additional 1 mL of prewarmed assay buffer, and further incubatedfor another 5 minutes. A final 5-minute incubation was carried out in asimilar manner. The same procedure was repeated with the inclusion of 10μL of the test compound (1 nM to 1 μM) and 10 μL ET-1 (0.3 nM), and theincubation was extended for 30 minutes. This solution was thencollected, 10 μL of scintillation cocktail was added, and the amount of[³H]arachidonic acid was determined in a liquid scintillation counter.

Further functional antagonism is demonstrated by the in vitro antagonismof ET-1 stimulated vasoconstriction (VERA-A) in the rabbit femoralartery. This assay is run according to the following literaturereference (Doherty A. M., Cody W. L.; He J. X., et al.). In vitro and invivo studies with a series of hexapeptide endothelin antagonists. J.Cardiovasc. Pharmacol., 1993:22(Suppl. 8):S98-102. The data arepresented as pA2 values.

The data in Table I below shows the endothelin receptor binding andantagonists activity of representative compounds of the instantinvention.

TABLE I Example HERBA-A^(a) HERBA-B^(a) VERA-A^(c) 1 >100 >2500 2 0.32300 6.9 3 2.0 >2500 4 1.0 >2500 7.0 5 0.3 >250 6 2.0 >2500 7 1.0 >25009 180 >25000 10 0.6 >2500 7.0 11 0.5 >2500 6.2 12 0.2 >250 13 2.0 >250014 0.2 2300 6.9 16 2.0 >2500 — 17 12.5 >2500 18 12 >2500 19 11.5 2200 203.3 1600 6.2 21 2.0 >2500 — 22 12 >2500 23 10 >2500 26 0.2 1900 7.8 2714 3350 28 12 4100 29 40 17000 30 180 >2500 31 2.0 2700 32 4.0 900 331.2 470 6.7 34 0.6 110 35 1.0 210 — 36 2.0 300 37 0.2 2300 6.9 38 1.0800 7.0 ^(a)IC₅₀ values in nM ^(b)Human cloned receptor data ^(c)pA₂values

As can be seen in Table I above, a representative compound of Formula Ibinds to the endothelin receptors ET_(A) (HERBA-A) in the μM to nMrange.

Table II presents representative examples displaying the excellent watersolubility attained with these agents.

TABLE II Example Aqueous Solubility 11 >25 mg/mL 37 >25 mg/mL 26 >80mg/mL

GENERAL SYNTHETIC APPROACHES

The compounds of Formula I may be prepared by several methods. In SchemeI, condensation of an aldehyde with an acetophenone-type compound inbasic solution such as alcoholic sodium hydroxide. This gives a chalconederivative which is treated with HCN in a solvent such as aqueousalcohol to give the nitrile. The nitrile is hydrolyzed to the ester withan acidic solution such as HCl/MeOH/H₂O. The ester is then condensed andcyclized with another aldehyde in a solvent such as methanol using abase such as sodium methoxide.

In Scheme II the chalcone from Scheme I is treated with the anion oftriphenylorthothioformate in an organic solvent such as THF. Thiscompound is then converted to a keto ester with a mix of mercury saltsby warming in an alcoholic solvent such as ethanol. The keto ester canthen be converted to compound, of Formula I as in Scheme I.

Additionally, the compounds of Formula I may be prepared by Scheme III.In Scheme III, a butenolide with a leaving group, such as halogen,mesylate, tosylate, or triflate, at either R₁, R₂, or R₃ (R₂ shown) istreated with a primary amine, secondary amine, or sodium sulfite to givea compound of Formula I, where Y′ is a secondary amine, tertiary amine,or sulfonic acid.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antagonists of endothelin, the compounds utilizedin the pharmaceutical method of this invention are administered at theinitial dosage of about 0.01 mg to about 100 mg/kg daily. A daily doserange of about 0.01 mg to about 10 mg/kg is preferred. The dosages,however, may be varied depending upon the requirements of the patient,the severity of the condition being treated, and the compound beingemployed. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

The following nonlimiting examples illustrate the methods for preparingthe compounds of the invention.

EXAMPLE 1

3-Benzo[1,3]dioxol-5-yl-4-[4-(3-dimethylamino-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one.hydrocloride

To methanol (12 mL) was added sodium metal (97 mg, 4.2 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.37 g, 4.0 mmol) then p-(3-dimethylaminopropoxy)benzaldehyde(870 mg, 4.0 mmol). The mixture was heated to reflux for 24 hours. Thesolution was then treated with acetic acid (2 mL) and refluxed anadditional 24 hours. The solvents were removed by evaporation, and theresidue was partitioned between ethyl acetate (50 mL) and water (100mL). The organic phase was separated and dried over magnesium sulfateand evaporated to dryness. The crude product was then purified by flashchromatography (350 g silica gel, 15% MeOH/CH₂Cl₂). The butenolide wasisolated by evaporation of the appropriate fractions to give 371 mg of awhite foam. This was treated with 179 μL of 4N HCl in dioxane (0.717mol) in dioxane (5 mL). The solution evaporated to a solid. The solidco-evaporated with ether to give a white foam, 395 mg (18%). Thebutenolide was identified by ¹H NMR, IR, MS, [M+H]⁺=518 Da., andmicroanalysis.

EXAMPLE 2

3-Benzol[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5(2-morpholin-4-yl-ethoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (10 mL) was added sodium metal (71 mg, 3.1 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.03 g, 3.0 mmol) then3-(2-N-morpholinyl-ethoxy)-4,5-dimethoxy-benzaldehyde (0.92 g, 3.1mmol). The mixture was heated to reflux for 24 hours. The solution wasthen treated with acetic acid (1 mL) and refluxed an additional 24hours. The solvents were removed by evaporation, and the residue waspartitioned between ethyl acetate (50 mL) and water (50 mL). The organicphase was separated and dried over magnesium sulfate and evaporated todryness. The crude product was then purified by flash chromatography(125 g silica gel, 4% methanol/methylene chloride). The butenolide wasisolated by evaporation of the appropriate fractions to give 350 mg(19%) as a white foam. The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=606 Da. and microanalysis.

INTERMEDIATE 1

To ethanol (10 mL) was added sodium metal (97 mg, 4.2 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.37 g, 4.0 mmol) then 3-(ethylacetoxy)-4,5-dimethoxybenzaldehyde(1.10 g, 4.1 mmol). The mixture was heated to reflux for 18 hours. Thesolution was then treated with acetic acid (3 mL) and refluxed anadditional 24 hours. The solvents were removed by evaporation, and theresidue was partitioned between ethyl acetate (75 mL) and water (75 mL).The organic phase was separated and dried over magnesium sulfate andevaporated to dryness. The crude product was then purified by flashchromatography (150 g silica gel, 20% ethyl acetate:methylene chloride).The butenolide was isolated by evaporation of the appropriate fractionsto give 410 mg (18%) as an oil. The butenolide was identified by ¹H NMR,IR, MS, [M+H]⁺=579 Da., and microanalysis.

INTERMEDIATE 2{5-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-aceticacid

In methanol (15 mL) was dissolved the butenolide, Intermediate 1, andthe solution treated with 1.010N sodium hydroxide (0.13 mL, 1.14 mmol),and the solution warmed to reflux for 24 hours. The mixture cooled toroom temperature and evaporated free of methanol. The residue waspartitioned between water (50 mL) and ether (50 mL). The aqueous phasewas separated and washed with ether (50 mL) and ethyl acetate (50 mL).The aqueous phase was made acidic and extracted with fresh ethyl acetate(2×30 mL). The combined final extraction phases evaporated in vacuo togive an oil, 295 mg (94%). The butenolide was identified by ¹H NMR, IR,MS, [M+H]⁺=551 Da., and microanalysis.

EXAMPLE 3

2-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-N-(2-morpholin-4-yl-ethyl)-acetamide

In DMF (8 mL) was dissolved the acid (Intermediate 2) (600 mg, 1.1mmol), HOBT (162 mg, 1.2 mol), and DCC (248 mg, 1.2 mmol). To this wasadded N-2-aminoethyl-morpholine (156 mg, 1.2 mmol). The mixture stirredat room temperature overnight. The solution filtered free of insolublesand the filtrate evaporated to a paste. The paste dissolved in ethylacetate (75 mL) and washed successively with water (100 mL) and brine(50 mL). The organic phase dried over MgSO₄ and evaporated in vacuo togive a foam. The foam was purified by flash chromatography (100 g flashsilica gel, 2-5% methanol/methylene chloride). Evaporation of theappropriate fractions gave 430 mg (54%) of a white solid which wasidentified by ¹H NMR, IR, MS, [M+H]⁺=663 Da., and microanalysis.

EXAMPLE 4

2-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl])-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethyl-phenoxy}-N-(2-morpholin-4-yl-ethyl)-acetamide2-hydroxythanesulfonate

In methanol (10 mL) was dissolved Example 3 (290 mg, 0.437 mmol) andisethionic acid (105 μL of 0.42N (aq.) solution, 0.437 mmol). Theresidue stirred for 5 minutes and evaporated in vacua The residuetriturated with ether (50 mL) and filtered to collect the solid, 340 mg(99%). The product was identified by ¹H NMR, IR, MS, [M+H]⁺=662 Da., andmicroanalysis.

EXAMPLE 5

3-Benzo[1,3]-dioxol-5-yl-4-[3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one2-hydroxy-1,2,3-propanetricarboxylate (1:1)(salt)

In a manner similar to Example 4, Example 2 (135 mg, 0.223 mmol) wasconverted to the salt with citric acid (43 mg, 0.223 mmol). This gave155 mg (87%) which was identified by ¹H NMR, IR, MS, [M+H]⁺=606 Da., andmicroanalysis.

EXAMPLE 6

3-Benzo-[1,3]dioxol-5-yl-[3-(3-dimethylamino-propoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (10 mL) was added sodium metal (71 mg, 3.1 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.03 g, 3.0 mmol) then3-(3-dimethylamino)propoxy-4,5-dimethoxybenzaldehyde (829 mg, 3.1 mmol).The mixture was heated to reflux for 24 hours. The solution was thentreated with acetic acid (1 mL) and refluxed an additional 24 hours. Thesolvents were removed by evaporation, and the residue was partitionedbetween very warm ethyl acetate (50 mL) and water (100 mL). The organicphase was separated and dried over magnesium sulfate and evaporated todryness. The crude product was then purified by flash chromatography(120 g silica gel, 5-20% methanol/methylene chloride). The butenolidewas isolated by evaporation of the appropriate fractions to give 75 mg(4%) as a white solid. The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=578 Da., and microanalysis.

EXAMPLE 7

3-Benzo[1,3]dioxol-5-yl-4-[3-(3-dimethylaminopropoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one2-hydroxyethanesulfonate

In a manner similar to Example 4, Example 6 (312 mg, 0.540 mmol) wasconverted to the salt with isethionic acid (1.19 mL of 0.42N (aq.), 0.50mmol). This gave 300 mg (85%) which was identified by ¹H NMR, IR, MS,[M+H]⁺=578 Da., and microanalysis.

EXAMPLE 8

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-4-[3-methoxy-4,5-bis-(2-morpholin-4-yl-ethoxy)-benzyl]-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (10 mL) was added sodium metal (45 mg, 1.95 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (651 mg, 1.90 mmol) then3,4-bis(2-N-morpholinylethoxy)-5-methoxy-benzaldehyde (780 mg, 1.97mmol). The mixture was heated to reflux for 24 hours. The solution wasthen treated with acetic acid (1 mL) and refluxed an additional 24hours. The solvents were removed by evaporation, and the residue waspartitioned between ethyl acetate (100 mL) and water (50 mL). Theorganic phase was separated and dried over magnesium sulfate andevaporated to dryness. The crude product was then purified by flashchromatography (150 g silica gel, 10% methanol/methylene chloride). Thebutenolide was isolated by evaporation of the appropriate fractions togive 309 mg (44w) as a thick oil. The butenolide was identified by ¹HNMR, IR, MS, [M+H]⁺=704518 Da., and microanalysis.

EXAMPLE 9

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-4-[3-methoxy-4,5-bis-(2-morpholin-4-yl-ethoxy)-benzyl]-5(4-methoxy-phenyl)-5H-furan-2-one2-hydroxyethanesulfonate

In a manner similar to Example 4, Example 8 (76 mg, 0.108 mmol) wasconverted to the salt with isethionic acid (0.514 mL of 0.42N (aq.),0.216 mmol). This gave 160 mg (77%) which was identified by ¹H NMR, IR,MS, [M+H]⁺=705 Da., and microanalysis.

EXAMPLE 10

3-Benzo[1,3]dioxol-5-yl-4-[3-(2-dimethylamino-ethoxy)-4,5-dimethoxy-benzyl-]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (10 mL) was added sodium metal (97 mg, 4.2 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.37 g, 4.0 mmol) then3-(2-dimethylaminoethoxy-4,5-dimethoxybenzaldehyde (1.04 g, 4.1 mmol).The mixture was heated to reflux for 24 hours. The solution was thentreated with acetic acid (1 mL) and refluxed an additional 24 hours. Thesolvents were removed by evaporation, and the residue was partitionedbetween warm ethyl acetate (75 mL) and water (50 mL). The organic phasewas separated and dried over magnesium sulfate and evaporated todryness. The crude product was then purified by flash chromatography(150 g silica gel, 10-15% methanol/methylene chloride). The butenolidewas isolated by evaporation of the appropriate fractions to give 1.05 g(47%) as a white foam. The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=564 Da., and microanalysis.

EXAMPLE 11

3-Benzo[1,3]dioxyl-5-yl-4-[3-(2-dimethylamino-ethoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one2-hydroxyethanesulfonate

In a manner similar to Example 4, Example 10 (363 mg, 0.644 mmol) wasconverted to the salt with isethionic acid (1.53 mL of 0.42N (aq.),0.644 mmol). This gave 300 mg (68%) which was identified by ¹H NMR, IR,MS, [M+H]⁺=564 Da., and microanalysis.

EXAMPLE 12

3-Benzo[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5-(3-morphlin-4-yl-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl-)-5H-furan-2-one

To methanol (10 mL) was added sodium metal (117 mg, 5.1 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.71 g, 5.0 mmol) then3-(3-N-morpholinyl-propoxy)-4,5-dimethoxybenzaldehyde (1.55 g, 5.0mmol). The mixture was heated to reflux for 24 hours. The solution wasthen treated with acetic acid (1 mL) and refluxed an additional 24hours. The solvents were removed by evaporation, and the residue waspartitioned between ethyl acetate (75 mL) and water (50 mL). The organicphase was separated and dried over magnesium sulfate and evaporated todryness. The crude product was then purified by flash chromatography(150 g silica gel, 5% methanol/methylene chloride). The butenolide wasisolated by evaporation of the appropriate fractions to give 560 mg(18%) as a foam. The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=619 Da., and microanalysis.

EXAMPLE 13

3-Benzo[1,3]dioxol-5-yl-4-{3,4-dimethoxy-5-[3-(4-methyl-piperazin-1-yl]-propoxy-benzyl}-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (10 mL) was added sodium metal (97 mg, 4.2 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.37 g, 4.0 mmol) then3-((3-(N′-methyl)-N-piperazinyl)propoxy)-4,5-dimethoxybenzaldehyde (1.32g, 4.1 mmol). The mixture was heated to reflux for 24 hours. Thesolution was then treated with acetic acid (1 mL) and refluxed anadditional 24 hours. The solvents were removed by evaporation, and theresidue was partitioned between ethyl acetate (100 mL) and water (50mL). The organic phase was separated and dried over magnesium sulfateand evaporated to dryness. The crude product was then purified by flashchromatography (150 g silica gel, 5-20% methanol/methylene chloride).The butenolide was isolated by evaporation of the appropriate fractionsto give 600 mg (24%) as a white foam. The butenolide was identified by¹H NMR, IR, MS, [M+H]⁺=633 Da., and microanalysis.

EXAMPLE 14

3-Benzo[1,3]dioxol-5-yl-4-{3,4-dimethoxy-5-[3-morpholin-4-yl-propoxy)-benzyl}5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one2-hydroxyethanesulfonate

In a manner similar to Example 4, Example 12 (360 mg, 0.581 mmol) wasconverted to the salt with isethionic acid (1.38 mL of 0.42N (aq.),0.581 mmol). This gave 465 mg (100w) which was identified by ¹H NMR, IR,MS, [M+H]⁺=619 Da., and microanalysis.

EXAMPLE 15

3-Benzo[1,3]dioxol-5-yl-4-{3,4-dimethoxy-5-[3-(4-methyl-piperazin-1-yl)-propoxyl-benzyl}-5-hydroxy-5-(4-methoxy-phenyl-5H-furan-2-one2-hydroxyethanesulfonate

In a manner similar to Example 4, Example 13 (430 mg, 0.679 mmol) wasconverted to the salt with isethionic acid (1.6 mL of 0.42N (aq.), 0.68mmol). This gave 328 mg (64%) which was identified by ¹H NMR, IR, MS,[M+H]⁺=633 Da., and microanalysis.

EXAMPLE 16

3-(3,5-Dimethoxy-phenyl])-4-[3-(2-dimethylamino-ethoxy)-4,5-dimethoxy-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (12 mL) was added sodium metal (42 mg, 1.84 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (649 mg, 1.81 mmol) then3-(3-dimethylamino)propoxy-4,5-dimethoxy-benzaldehyde (460 mg, 1.81mmol). The mixture was heated to reflux for 24 hours. The solution wasthen treated with acetic acid (1 mL) and refluxed an additional 24hours. The solvents were removed by evaporation, and the residue waspartitioned between ethyl acetate (100 mL) and water (60 mL). Theorganic phase was separated and dried over magnesium sulfate andevaporated to dryness. The crude product was then purified by flashchromatography (150 g silica gel, 10-20% methanol/methylene chloride).The butenolide was isolated by evaporation of the appropriate fractionsto give 385 mg (37%) as a foam. The butenolide was identified by ¹H NMR,IR, MS, [M+H]⁺=580 Da., and microanalysis.

EXAMPLE 17

4-{3,4-Dimethoxy-5-[3-(4-methyl-piperazzin-1-yl)-propoxy]-benzyl}-3-(3,5-dimethoxy-phenyl)-5-hydroxy-5-(4-methoxy-phenyl)-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (12 mL) was added sodium metal (74 mg, 3.2 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.11 g, 3.1 mmol) then3-((3-(N′-methyl)-N-piperazinyl)propoxy)-4,5-dimethoxybenzaldehyde (1.0g, 3.1 mmol). The mixture was heated to reflux for 24 hours. Thesolution was then treated with acetic acid (2 mL) and refluxed anadditional 24 hours. The solvents were removed by evaporation, and theresidue was partitioned between ethyl acetate (100 mL) and water (60mL). The organic phase was separated and dried over magnesium sulfateand evaporated to dryness. The crude product was then purified by flashchromatography (125 g silica gel, 15-20% methanol/methylene chloride).The butenolide was isolated by evaporation of the appropriate fractionsto give 840 mg (42%) as a foam. The butenolide was identified by ¹H NMR,IR, MS, [M+H]⁺=648 Da., and microanalysis.

EXAMPLE 18

3-Benzo[1,3]dioxol-5-yl-4-[3-(3-dimethylamino-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (50 mL) was added sodium metal (0.89 g, 38.7 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (10.61 g, 31.0 mmol) then 3-(3-dimethylaminopropoxy)-benzaldehyde(8.03 g, 38.7 mmol). The mixture was heated to reflux for 5 hours. Thesolution was then treated with acetic acid (6.3 mL) and refluxed anadditional 15 hours. The solvents were removed by evaporation, and theresidue was partitioned between warm ethyl acetate (250 mL) and water(50 mL). The organic phase was separated and dried over magnesiumsulfate and evaporated to dryness. The crude product was then purifiedby flash chromatography (silica gel, 5% EtOAc in CH₂Cl₂). The butenolidewas isolated by evaporation of the appropriate fractions to give 10.61 g(66.1%) as a white foam. The butenolide was identified by ¹H NMR, IR,MS, [M+H]⁺=518 Da., and microanalysis.

EXAMPLE 19

3-Benzo[1,3]dioxol-5-yl-4-[3-(2-dimethylamino-ethoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (50 mL) was added sodium metal (0.84 g, 36.5 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (10.00 g, 29.2 mmol) then 3-(2-dimethylaminoethoxy)-benzaldehyde(7.06 g, 36.5 mmol). The mixture was heated to reflux for 5 hours. Thesolution was then treated with acetic acid (6.3 mL) and refluxed anadditional 15 hours. The solvents were removed by evaporation, and theresidue was partitioned between warm ethyl acetate (250 mL) and water(50 mL). The organic phase was separated and dried over magnesiumsulfate and evaporated to dryness. The crude product was then purifiedby flash chromatography (silica gel, 5% EtOAc/CH₂Cl₂). The butenolidewas isolated by evaporation of the appropriate fractions to give 4.30 g(29%) as a white foam. The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=504 Da., and microanalysis.

EXAMPLE 20

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(methyl-phenyl)-4-[3-(2-morpholin-4-yl-ethoxy)-benzyl]-5H-furan-2-one

To methanol (50 mL) was added sodium metal (0.84 g, 36.5 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (10.00 g, 29.2 mmol) then 3-(2-morpholinoethoxy)-benzaldehyde(8.60 g, 36.5 mmol). The mixture was heated to reflux for 5 hours. Thesolution was then treated with acetic acid (6.3 mL) and refluxed anadditional 15 hours. The solvents were removed by evaporation, and theresidue was partitioned between warm ethyl acetate (250 mL) and water(50 mL). The organic phase was separated and dried over magnesiumsulfate and evaporated to dryness. The crude product was then purifiedby flash chromatography (silica gel, 5% EtOAc/CH₂Cl₂). The butenolidewas isolated by evaporation of the appropriate fractions to give 12.00 g(75%) as a creamy foam. The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=546 Da., and microanalysis.

EXAMPLE 21

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-[3-(3-morpholin-4-yl-propoxy)-benzyl]-5H-furan-2-one

To methanol (20 mL) was added sodium metal (322 mg, 14.00 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (4.37 g, 12.76 mmol) then 3-(3-morpholinopropoxy)benzaldehyde(3.18 g, 12.76 mmol). The mixture was heated to reflux for 5 hours. Thesolution was then treated with acetic acid (2.8 mL) and refluxed anadditional 15 hours. The solvents were removed by evaporation. Theresidue was stirred in EtOAc (150 mL) and then water (100 mL). Whitesolid was collected by filtration, washed again with H₂O, followed byEt₂O with a little THF. Dry in vacuum to give 3.05 g of the desiredcompound (43%). The butenolide was identified by ¹H NMR, IR, MS,[M+H]⁺=560 Da., and microanalysis.

EXAMPLE 22

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-{3-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-5H-furan-2-one

To methanol (10 mL) was added sodium metal (132 mg, 5.74 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (1.57 g, 4.58 mmol) then3-(3-(4-methylpiperazino)propoxy)-benzaldehyde (1.20 g, 4.5 mmol). Themixture was heated to reflux for 5 hours. The solution was then treatedwith acetic acid (0.75 mL) and refluxed an additional 15 hours. Thesolvents were removed by evaporation, and the residue was partitionedbetween warm ethyl acetate (100 mL) and water (30 mL). The organic phasewas separated and dried over magnesium sulfate and evaporated todryness. The crude product was then purified by flash chromatography(silica gel, 10% MeOH/CH₂Cl₂). The butenolide was isolated byevaporation of the appropriate fractions to give 1.55 g (459) as a whitefoam. The butenolide was identified by ¹H NMR, IR, MS, [M+H]⁺=573 Da.,and microanalysis.

EXAMPLE 23

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-[3-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-5H-furan-2-one

To methanol (15 mL) was added sodium metal (210 mg, 9.13 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester (2.50 g, 7.30 mmol) then 3-(2-pyrrolidinoethoxy)benzaldehyde (2.00g, 9.12 mmol). The mixture was heated to reflux for 5 hours. Thesolution was then treated with acetic acid (1.2 mL) and refluxed anadditional 15 hours. The solvents were removed by evaporation, and theresidue was partitioned between warm ethyl acetate and water. Theorganic phase was separated and dried over magnesium sulfate andevaporated to dryness. The crude product was then purified by flashchromatography (silica gel, 3-5% MeOH/CH₂Cl₂). The butenolide wasisolated by evaporation of the appropriate fractions to give 2.46 g(64%) as a white powder. The butenolide was identified by IH NMR, IR,MS, [M+H]⁺=530 Da., and microanalysis

INTERMEDIATE 3

To 4-methoxyacetophenone 2.20 g (14.1 mmol) in absolute ethanol (7.0 mL)in an erlenmeyer was added3-methoxy-5-(2-dimethylaminoethoxy)benzaldehyde 2.92 g (13.1 mmol) inabsolute ethanol (3.0 mL). The solution was stirred while 10% sodiumhydroxide (0.45 mL) added. The mixture was stirred for 4 hours. Thesolvent was evaporated and the residue partitioned between ethyl acetate(50 mL) and water (50 mL). The organic phase was separated and theaqueous extracted with additional ethyl acetate (50 mL). The organiclayers were combined, dried over magnesium sulfate, and evaporated invacuo to a red oil which was flash chromatographed on silica gel (2%methanol/chloroform) to give the chalcone 4.03 g (896%) as a yellow oilwhich was identified by ¹H NMR and MS.

INTERMEDIATE 4

To the chalcone, Intermediate 3, 4.03 g (11.3 mmol) in 2-ethoxyethanol(15 mL) was added acetic acid (0.78 mL) and the solution heated to 110°C. Potassium cyanide 1.08 g (16.6 mmol) in water (4 mL) was slowlyadded, and the solution was stirred at 110° C. for 45 minutes. Thesolution was cooled and the solvent evaporated. The residue waspartitioned between ethyl acetate (75 mL) and water (75 mL). The organiclayer was separated, and the aqueous was extracted with ethyl acetate(2×75 mL). Combined organic layers, dried over magnesium sulfate andevaporated to a dark yellow oil. ¹H NMR indicated unreacted chalcone waspresent. The reaction was repeated as above with acetic acid (1.40 mL)and potassium cyanide 2.20 g (34.0 mmol). Heated 30 minutes and workedup as above to give the nitrile as a brown oil 4.76 g (>100%). Thenitrile was identified by ¹H NMR and MS. The product was used withoutpurification in the preparation of the ester.

INTERMEDIATE 5

To the crude nitrile, Intermediate 4, (11.3 mmol) was addedmethanol/p-dioxane (60/40, 40 mL) followed by the addition ofp-toluenesulfonic acid 2.15 g (11.3 mmol). The solution was heated toreflux for 18 hours. Additional p-toluenesulfonic acid 4.30 g (22.6mmol) was added and the heating continued for 6 hours. The solution wascooled and the solvent evaporated. The residue was dissolved in ethylacetate (100 mL) and washed with saturated sodium bicarbonate (2×100mL). The organic layer was dried over magnesium sulfate and evaporatedto give the ester 3.20 g (68% based on chalcone) as a red oil which wasidentified by ¹H NMR and MS.

EXAMPLE 24

3-[3-(2-Dimethylamino-ethoxy)-5-methoxy-phenyl]-5-hydroxy5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one

To methanol (20 mL) was added sodium metal 0.194 g (8.43 mmol) andstirred to dissolve. To this solution was added the ester, Intermediate5, 3.20 g (7.70 mmol) followed by 3,4,5-trimethoxybenzaldehyde 1.89 g(9.63 mmol). The mixture was heated to reflux for 24 hours. The solutionwas then treated with acetic acid (2.0 mL) and refluxed an additional 20hours. The solvent was removed by evaporation, and the residue waspartitioned between ethyl acetate (100 mL) and water (100 mL). AdjustedpH to 9.5 (5% NaOH) and removed organic layer. The aqueous layer wasadjusted to pH 7.0 (2 M HCl) and then extracted with ethyl acetate(2×100 mL). The organic layers were combined, dried over magnesiumsulfate, and evaporated to give a yellow foam which was flashchromatographed on silica gel 100 g (2-10% methanol/chloroform) to givethe butenolide 0.67 g (15%) as a light yellow foam which was identifiedby 1H NMR, MS, [M+H]⁺=580 Da. and microanalysis.

EXAMPLE 25

3-[3-(2-Dimethylamino-ethoxy)-5-methoxy-phenyl]-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one2hydroxyethanesulfonate

In a manner similar to Example 4, Example 24 (490 mg, 0.85 mmol) wasconverted to the salt with isethionic acid (2.00 mL of 0.42N (aq.), 0.84mmol). This gave 530 mg (90%) which was identified by ¹H NMR, MS,[M+H]⁺=580 Da., and microanalysis.

INTERMEDIATE 6

Sodium metal 0.449 g (19 mmol) was dissolved in absolute anhydrousethanol (50 mL). To the solution was added3-hydroxy-4,5-dimethoxybenzaldehyde 3.49 g (19 mmol), followed by asolution of 1,3-propane sultone 2.33 g (19 mmol) in ethanol (20 mL). Themixture was heated to reflux for 1.5 hours giving a solid. The solid wasfiltered, washed with ethanol and ethyl ether, and dried in vacuo, 5.67g, 91%, which was identified by ¹H NMR, MS, and microanalysis.

EXAMPLE 26

Sodium,5-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2(4-methoxy-phenyl)-5-oxo)-2,5-dihydro-furan-3-ylmethyl]2,3-dimethoxy-phenoxy}-propane-1-sulfonate

To methanol 50 mL was added sodium metal 0.27 g (11.80 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester, 3.85 g (11.25 mmol) then (12.93 mmol). The mixture was heated toreflux for 16 hours. The solution was then treated with acetic acid (5mL) and refluxed an additional 16 hours. The solvents were removed byevaporation, and the residue was partitioned between ether (100 mL) andwater (50 mL). The aqueous phase was acidified with 8N HCl, giving anoily precipitate. The oil was separated and purified by chromatographyon silica gel (50 g), eluted with 20% methanol in chloroform. A solidwas recovered by addition of ethyl ether to the concentrate of theappropriate fractions, 0.697 g (9.7%). The butenolide was recovered asthe 1/3 Na. salt and identified by ¹H NMR, MS, [M+H]⁺=613.3 Da., andmicroanalysis.

The following compounds are prepared in a similar manner:3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-butane-1-sulfonicacid;3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-ethane-1-sulfonicacid; and3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-.(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-pentane-1-sulfonicacid.

INTERMEDIATE 7

To 2-hydroxy-4-methoxyacetophenone 20 g (120 mmol) in dimethyl formamide(250 mL) was added cesium carbonate 97.6 g (299 mmol) and3-chloropropyl-dimethylamine hydrochloride 31.6 g (200 mmol). Thesolution was warmed to 90° C. for 3.5 hours followed by stirring at 25°C. for 48 hours. The mixture was filtered and evaporated to an oil invacuo. The oil was partitioned between ethyl ether and water, and theether phase was extracted with 2N HCl. The acid extract was layered withethyl ether, and the pH of the aqueous phase was adjusted to 14 with 25%sodium hydroxide solution. The organic phase was washed with brine,dried over magnesium sulfate, filtered, and evaporated in vacuo to anoil, 22.04 g (73%), which was identified by ¹H NMR, MS, andmicroanalysis.

INTERMEDIATE 8

To 3,4-methylenedioxybenzaldehyde 10.7 g (71.3 mmol) in absolute ethanol(100 mL) in an erlenmeyer was added Intermediate 7, 17.92 g (71.3 mmol).The solution was warmed while 12.5% sodium hydroxide (10 mL) added. Themixture was refluxed for 2 hours and evaporated in vacuo to an oil. Themixture was partitioned between ethyl ether and 1N HCl. The organicphase was separated and the pH of the aqueous phase was adjusted to 9with 6N sodium hydroxide. The aqueous phase was extracted with ethylether, which was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and evaporated in vacuo to an oil, 25.99 g (95%),which was identified by ¹H NMR, MS, and microanalysis.

INTERMEDIATE 9

To the chalcone, Intermediate 8, 25.87 g (67 mmol) in 2-ethoxyethanol(100 mL) at 80° C. was added acetic acid (8.86 g) followed by slowaddition of potassium cyanide 13.75 g (211 mmol) in water 20 mL. Thesolution was stirred at 120° C. for 0.5 hours. The solution was cooledover 18 hours giving a solid. The solid was filtered, washed with 50/50ethanol/water followed by washing with ethyl ether. The solid was driedin vacuo, 229 (79%). The nitrile was identified by ¹H NMR, MS, andmicroanalysis.

INTERMEDIATE 10

To the nitrile, Intermediate 9, 21.75 g (53.1 mmol) was added methanol(180 mL) and dioxane (120 mL). To the mixture was addedp-toluenesulfonic acid monohydrate 29.1 g (153 mmol). The mixture washeated to reflux for 48 hours and evaporated to a glassy solid. Theresidue was suspended in ethyl acetate and washed with saturated sodiumbicarbonate solution and brine. The organic phase was washed with brine,dried over magnesium sulfate, and evaporated in vacuo to a small volume.The residue was triturated with ethyl ether, giving a solid which wasthen filtered and dried in vacuo, 18.43 g (78%), identified by ¹H NMR,MS, and microanalysis.

INTERMEDIATE 11

To 3,4-methylenedioxybenzaldehyde 7.51 g (50 mmol) in absolute ethanol(50 mL) in an erlenmeyer was added 4-hydroxyacetophenone 6.81 g (50mmol). The solution was warmed while 12.5% sodium hydroxide (20 mL)added. The mixture was refluxed for 1 hour and allowed to standovernight at 25° C. The pH was adjusted to 4 with 6N HCl, giving aprecipitate. The solid was collected by filtration and washed withwater. The solid was dissolved in ethyl acetate, washed with brine, anddried over anhydrous magnesium sulfate. The solution was evaporated invacuo to a small volume, and the product was precipitated by addition ofpetroleum ether. The solid was filtered and dried in vacuo giving 9.25 gof a yellow solid, mp 200-204° C., which was identified by ¹H NMR, MS,and microanalysis.

INTERMEDIATE 12

To the chalcone, Intermediate 11, 8.0 g (29.8 mmol) in dimethylformamide(75 mL) was added cesium carbonate 46 g (144 mmol) followed by additionof 2-chloroethylmorpholine 7.95 g (69.0 mmol). After heating at 90° C.for 2 hours, the mixture solidified. The paste was filtered, washed withdimethylformamide, and the filtrates were evaporated to a solid invacuo. The solid was dissolved in ethyl acetate, and washed with iNNaOH, and brine. The organic phase was dried over magnesium sulfate,filtered, and evaporated in vacuo to a small volume giving aprecipitate. The paste was filtered, washed with ethyl ether, and driedin vacuo giving a solid, 9.0 g, mp 125-126° C. The chalcone wasidentified by ¹H NMR, MS, and microanalysis.

INTERMEDIATE 13

To the chalcone, Intermediate 12, 8.75 g (22.9 mmol) in 2-ethoxyethanol(45 mL) at 80° C. was added acetic acid (3.02 g) followed by slowaddition of potassium cyanide 4.68 g (71.8 mmol) in water (10 mL). Thesolution was stirred at 120° C. for 0.5 hours. The solution was cooledover 1 hour and evaporated to an oil. The oil was suspended in ethylether, and extracted with water. The water extract was adjusted to pH 13with 1N sodium hydroxide solution and extracted exhaustively with ethylacetate. The organic phase was washed with brine, dried over magnesiumsulfate, filtered, and evaporated in vacuo to an oil, 10.9 g (74%). Thenitrile was identified by ¹H NMR, MS, and microanalysis.

INTERMEDIATE 14

To the nitrile, Intermediate 13, 10.8 g (22.0 mmol) was added methanol(75 mL) and dioxane (75 mL). To the mixture was added p-toluenesulfonicacid monohydrate 12 g (63.1 mmol). The mixture was heated to reflux for48 hours and evaporated to a glassy solid. The residue was suspended inethyl acetate and washed with saturated sodium bicarbonate solution andbrine. The organic phase was extracted with 1N HCl which was separatedfrom the organic phase. The acid extract was then extracted with ethylacetate, while the mixture was made basic by the addition of saturatedsodium bicarbonate. The organic phase was washed with brine, dried overmagnesium sulfate, and evaporated in vacuo to a small volume. Theresidue was triturated with a mixture of ethyl ether and petroleumether, giving a solid which was then filtered and dried in vacuo, 6.62g, identified by ¹H NMR, MS, and microanalysis.

EXAMPLE 27

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-[4-(2-morpholin-4-ethoxy)-phenyl]-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one

To methanol (45 mL) was added sodium metal, 0.217 g (9.44 mmol) andstirred to dissolve. To this was added the ester, Intermediate 14, (3.97g, 9.0 mmol) then 3,4,5-trimethoxybenzaldehyde, 2.19 g (11.19 mmol). Themixture was heated to reflux for 18 hours. The solution was then treatedwith acetic acid (5 mL) and refluxed an additional 15 hours. Thesolvents were removed by evaporation, and the residue was partitionedbetween ether (100 mL) and 1 sodium hydroxide (100 mL). The aqueousphase was separated and acidified with 6N HCl . This acidic solution wasextracted with 100 mL ethyl ether. The organic phase was separated,washed with brine, dried over magnesium sulfate, and evaporated invacuo. This gave the butenolide 3.13 g (57%) as a solid. The butenolidewas identified by 1H NMR, MS, [M+H]⁺=606 Da., and microanalysis.

EXAMPLE 28

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one2-hydroxyethanesulfonate

To methanol (5 mL) was added the butenolide, Example 27, 0.605 g (1.0mmol) giving solution, followed by addition of 0.42N isethionic acid(2.38 mL). The mixture was evaporated in vacuo to a gum. The gum wasdissolved in water (25 mL), filtered at 45 microns, and lyophilized to asolid, 0.717 g, which was identified by ¹H NMR, MS, and microanalysis.

INTERMEDIATE 15

To 3,4-methylenedioxybenzaldehyde 7.51 g (50 mmol) in absolute ethanol(50 mL) in an Erlenmeyer was added 4-hydroxyacetophenone 6.81 g (50mmol). The solution was warmed while 12.5% sodium hydroxide (20 mL)added. The mixture was refluxed for 1 hour and allowed to standovernight at 25° C. The pH was adjusted to 4 with 6N HCl, giving aprecipitate. The solid was collected by filtration and washed withwater. The solid was dissolved in ethyl acetate, washed with brine, anddried over anhydrous magnesium sulfate. The solution was evaporated invacuo to a small volume, and the product was precipitated by addition ofpetroleum ether. The solid was filtered and dried in vacuo giving 9.25 gof a yellow solid, mp 200-204° C., which was identified by ¹H NMR, MS,and microanalysis.

INTERMEDIATE 16

To the chalcone, Intermediate 15, 8.0 g (29.8 mmol) in dimethylformamide(200 mL) was added cesium carbonate 48.0 g (147 mmol) followed byaddition of 3-chloropropyldimethylamine hydrochloride 11.78 g (74.5mmol). After heating at 90° C. for 2 hours, the mixture was filtered andevaporated to an oil in vacuo. The oil was dissolved in ethyl acetate,and a solid was precipitated by the addition of 1N HCl. The liquidphases were decanted, and the solid was partitioned between ethylacetate and 2N NaOH, giving solution of the solid. The organic phase waswashed with brine, dried over magnesium sulfate, filtered, andevaporated in vacuo to a small volume. Addition of ethyl ether gave aprecipitate which was filtered, washed with ethyl ether, and dried invacuo giving a solid, 6.6 g. The chalcone was identified by ¹H NMR, MS,and microanalysis.

INTERMEDIATE 17

To the chalcone, Intermediate 16, 6.5 g (18.39 mmol) in 2-ethoxyethanol(50 mL) at 100° C. was added acetic acid 2.66 g (44 mmol) followed byslow addition of potassium cyanide 5.25 g (80.6 mmol) in water (25 mL).The solution was stirred at 120° C. for 20 minutes. The solution wascooled over 1 hour and evaporated in vacuo to a paste. The paste wassuspended in a mixture of ethyl acetate and ethyl ether, and filtered.The filtered solid was partitioned between ethyl acetate and watergiving solution of the paste. The aqueous phase was extractedexhaustively with ethyl acetate. The organic extract was washed withbrine, dried over magnesium sulfate, filtered, and evaporated in vacuoto an oil, 6.11 g. The nitrile was identified by ¹H NMR, MS, andmicroanalysis.

INTERMEDIATE 18

To the nitrile, Intermediate 17, 8.11 g (18.4 mmol) was added methanol(60 mL) and dioxane (40 mL). To the mixture was added p-toluenesulfonicacid monohydrate 10 g (53 mmol). The mixture was heated to reflux for 48hours, and evaporated to an oil. The residue was suspended in ethylacetate and washed with saturated sodium bicarbonate solution and brine.The organic phase was washed with brine, dried over magnesium sulfate,and evaporated in vacuo to an oil, 5.9 g, identified by ¹H NMR, MS, andmicroanalysis.

EXAMPLE 29

3-Benzo[1,3]dioxol-5-yl-5-[4-(3-dimethylamino-propoxy)-phenyl]-5-hydroxy-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one

To methanol (50 mL) was added sodium metal 0.337 9 (36.5 mmol) andstirred to dissolve. To this was added the ester, Intermediate 18, 5.8 9(14.0 mmol) then 3,4,5-trimethoxybenzaldehyde 3.42 g (17.4 mmol). Themixture was heated to reflux for 18 hours. The solution was then treatedwith acetic acid (5 mL) and refluxed an additional 5 hours. The solventswere removed by evaporation, and the residue was partitioned betweenether (100 mL) and 1N sodium hydroxide (100 mL). The aqueous phase wasseparated and acidified to pH 8 with 6N HCl. This solution was extractedwith 100 mL ethyl acetate. The organic phase was separated, washed withbrine, dried over magnesium sulfate, and evaporated in vacuo). This gavethe butenolide 1.62 g (20%) as a solid. The butenolide was identified by¹H NMR, MS, [M+H]⁺=578 Da., and microanalysis.

EXAMPLE 30

3-Benzo[1,3]dioxol-5-yl-5-[4-(3-dimethylamino-propoxy)-phenyl]-5-hydroxy-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one2-hydroxyethanesulfonate

To methanol (5 mL) was added the butenolide, Example 29, 0.50 g (0.866mmol) giving solution, followed by addition of 0.42N isethionic acid(2.06 mL). The mixture was evaporated in vacuo to a gum. The gum wasdissolved in water (25 mL), filtered at 45 microns, and lyophilized to asolid, 0.56 g, which was identified by ¹H NMR, MS, and microanalysis.

INTERMEDIATE 19

To methanol (80 mL) was added sodium metal 0.48 9 (21 mmol) and stirredto dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester, 6.84 g (19.9 mmol) then m-nitrobenzaldehyde 3.48 g (23 mmol). Themixture was heated to reflux for 16 hours. The solution was then treatedwith acetic acid (9 mL) and refluxed an additional 15 hours. Thesolvents were removed by evaporation, and the resulting solid wassuspended in ethyl ether and water, filtered, washed with ether, anddried in vacuo to a solid, 7.73 g (84%). The butenolide was identifiedby ¹H NMR, MS, [M+H]⁺=462 Da., and microanalysis.

INTERMEDIATE 20

To tetrahydrofuran (75 mL) was added Raney Nickel paste 0.48 g (DavisonChemical, Lot 5125). To this was added the butenolide, Intermediate 19,0.412 g (0.893 mmol). The mixture was purged with H₂ for 2 hours. Thesolution was then filtered, evaporated in vacuo, and the residueresuspended in ethyl ether. Addition of hexane gave a white solid whichwas filtered and dried in vacuo, 0.322 g (84%). The butenolide wasidentified by IH NMR, MS, [M+H]⁺=432 Da., and microanalysis.

EXAMPLE 31

3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3-methylamino-benzyl)-5H-furan-2-one

To a mixture of 95% ethanol (45 mL) and tetrahydrofuran (30 mL) wasadded Raney Nickel paste 0.2 g (Davison Chemical) and 37% formaldehydesolution 0.1 g (1.11 mmol). To this was added the butenolide,Intermediate 20, 0.48 g (1.11 mmol). The mixture was pressurized with H₂gas at 30 psi for 18 hours. The solution was then filtered, evaporatedin vacuo, and the residue purified by chromatography on silica gel (50g), eluted with a gradient of 10% to 30% ethyl acetate in hexane.Addition of ethyl ether followed by drying in vacuo gave a white solid,0.23 g (46%). The butenolide was identified by ¹H NMR, MS, [M+H]⁺=445Da., and microanalysis.

INTERMEDIATE 21

Dimethylamine gas 32 g (718 mmol) was condensed into benzene (300 mL) at0° C., and 3-bromobenzyl bromide 54.99 (219;6 mmol) in benzene (100 mL)was then added. After stirring 48 hours at 25° C., the mixture waswashed with 4N sodium hydroxide solution and extracted with 4N HCl. Theextract was adjusted to pH 14 with 4N sodium hydroxide solution andextracted with ethyl ether. The ether phase was washed with brine, driedover magnesium sulfate, and filtered. The filtrate was evaporated invacuo to an oil, 45.9 g. The oil was distilled to a clear oil, 36.2 g,bp 78-84° C. at 0.75 mm Hg, which was identified by ¹H NMR, MS, andmicroanalysis.

INTERMEDIATE 22

To dry, tetrahydrofuran (100 mL) was added magnesium turnings 4.09 g(168 mmol) followed by the gradual addition of a solution ofIntermediate 21,36 g (168 mmol), in dry ethyl ether (75 mL). After 1hour the addition was complete, and the temperature was held at refluxfor 2 hours. The mixture was cooled to −50° C., and a solution ofdimethylformamide 12.28 g (168 mmol) in dry ethyl ether (75 mL) wasadded. The mixture was stirred at 25° C. for 18 hours, then poured into250 mL cold 6N HCl. The phases were separated, and the aqueous phase wasadjusted to pH 14 with 2N sodium hydroxide solution. The mixture wasextracted into ethyl ether and washed with brine, dried over magnesiumsulfate, and filtered. Evaporation under reduced pressure gave an oilwhich was purified by chromatography on 1300 g silica gel eluted with agradient of 50% hexane and 50% ethyl acetate to 20% methanol and 80%ethyl acetate. The product was distilled giving an oil, (18 g), bp80-85° C. at 1.5 mm Hg, which was identified by ¹H NMR, MS, andmicroanalysis.

EXAMPLE 32

3-Benzo[1,3]dioxol-5-yl-4-(3-dimethylaminoethyl-benzyl)-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (50 mL) was added sodium metal 0.271 g (11.8 mmol) andstirred to dissolve. To this was added the ester,2-Benzo[1,3]dioxol-5-yl-1-(4-methoxyphenyl)-4-oxo-butyric acid methylester, 3.85 g (11.25 mmol) then Intermediate 22, 2.11 g (12.93 mmol).The mixture was heated to reflux for 16 hours. The solution was thentreated with acetic acid (5 mL) and refluxed an additional 16 hours. Thesolvents were removed by evaporation, and the residue was partitionedbetween ether (100 mL) and water (100 mL). The aqueous phase wasadjusted to pH 13 with 2N sodium hydroxide, and was washed with ethylether. The aqueous phase was then acidified to pH 4 with 2N HCl giving asolid precipitate. The solid was filtered, washed with ethyl ether andwater, and partitioned between ethyl acetate and water at pH 10, givingsolution of the solid. The organic phase was washed with brine, driedover magnesium sulfate, and filtered. Evaporation of the solution invacuo gave a white foam, 2.75 g (52w). The butenolide was identified by¹H NMR, MS, [M+H]⁺=474 Da., and microanalysis.

EXAMPLE 33

3-Benzo[1,3]dioxol-5-yl-4-(3-dimethylaminomethyl-benzyl)-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one2-hydroxyethanesulfonate

To methanol (5 mL) was added the butenolide, Example 32, 0.473 g (1.0mmol) giving solution, followed by addition of 0.42N isethionic acid(2.33 mL). The mixture was evaporated in vacuo to a gum. The gum wasdissolved in water (25 mL), filtered at 45 microns, and lyophilized to asolid, 0.58 9, which was identified by ¹H NMR, MS, and microanalysis.

EXAMPLE 34

4-(3-Dimethylaminomethyl-benzyl)-5-hydroxy-3-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-5H-furan-2-one

To methanol (50 mL) was added sodium metal 0.271 g (11.8 mmol) andstirred to dissolve. To this was added the ester,2-[7-methoxy-benzo[1,3]dioxol]-5-yl-1-(4-methoxyphenyl)-4-oxo-butyricacid methyl ester, 4.19 g (11.25 mmol) then Intermediate 22, 2.11 g(12.93 mmol). The mixture was heated to reflux for 16 hours. Thesolution was then treated with acetic acid (5 mL) and refluxed anadditional 16 hours. The solvents were removed by evaporation, and theresidue was partitioned between ether (100 mL) and water (100 mL). Theaqueous phase was adjusted to pH 13 with 4N sodium hydroxide, giving anoily precipitate. Decant the oil and partition it between ethyl acetateand water. Adjust pH to 9 with 6N HCl, separate phases, and wash theorganic phase with brine. The organic phase was dried over magnesiumsulfate, filtered, and evaporated in vacuo to a small volume.Trituration with ethyl ether gave a white solid which was collected anddried in vacuo, 3.2 g. The butenolide was identified by ¹H NMR, MS,[M+H]⁺=504 Da., and microanalysis.

EXAMPLE 35

4-(3-Dimethylaminomethyl-benzyl)-5-hydroxy-3-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-5H-furan-2-one2-hydroxyethanesulfonate

To water (20 mL) was added the butenolide, Example 34, 0.568 g (1.0mmol) followed by addition of 0.42N isethionic acid (2.82 mL) givingsolution. The mixture was evaporated in vacuo to a gum. The gum wasdissolved in water (25 mL), filtered at 45 microns, and lyophilized to asolid, 0.654 g, which was identified by ¹H NMR, MS, and microanalysis.

EXAMPLE 36

3-(3-Dimethylaminomethyl-benzyl)-2-(7-methoxy-benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic-acidsodium salt

The butenolide, Example 34, 0.828 g (1.645 mmol) was added to 1.001Nsodium hydroxide (1.64 mL) giving solution, followed by dilution withwater to (25 mL). The solution was filtered at 45 microns, andlyophilized to a solid, 0.793 g, which was identified by ¹H NMR, MS, andmicroanalysis.

EXAMPLE 37

3-Benzo[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)-benzyl]-5-hydroxy-(4-methoxy-phenyl)-5-furan-2-one2-hydroxyethanesulfonate

In a manner similar to Example 4, Example 2 (230 mg, 0.380 mmol) wasconverted to the salt with isethionic acid (900 μL of 0.42 (aq.), 0.380mmol). This gave 260 mg (94%) which was identified by 1H NMR, IR, MS,[M+H]⁺=606 Da., and microanalysis.

EXAMPLE 38

3Benzo[1,3]dioxol-5-yl-5-[2-(3-dimethylamino-propoxy)-4-methoxy-phenyl]-5-hydroxy-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one

To methanol (50 mL) was added sodium metal 0.337 g (14.7 mmol) andstirred to dissolve. To this was added the ester, Intermediate 10, 6.21g (14.0 mmol) then 3,4,5-trimethoxybenzaldehyde 3.42 g (17.4 mmol). Themixture was heated to reflux for 16 hours. The solution was then treatedwith acetic acid (8 mL) and refluxed an additional 16 hours. Thesolvents were removed by evaporation, and the residue was partitionedbetween ether (100 mL) and water (100 mL) giving a suspension. Theaqueous phase was adjusted to pH 14 with 6N sodium hydroxide, givingsolution of the solids. The ether phase was decanted, and the aqueousphase was adjusted to pH 9 with 6N HCl, giving a precipitate. The solidwas filtered and washed with water and ethyl ether. The solid was driedin vacuo, 6.17 g. The solid was further purified by chromatography onsilica gel, 250 g, and eluted with a gradient of 5% to 10% methanol inchloroform. A solid was recovered from an ethyl acetate/ethyl ether,4.22 g (49%). The butenolide was identified by ¹H NMR, MS, [M+H]⁺=608Da., and microanalysis.

What is claimed is:
 1. A compound of formula

or a tautomeric open chain keto-acid form thereof or a pharmaceuticallyacceptable salt thereof wherein R₁ is cycloalkyl of from 3 to 12 carbonatoms substituted or unsubstituted, phenyl substituted with from 1 to 5substituents, naphthyl unsubstituted or substituted with from 1 to 5substituents, or heteroaryl unsubstituted or substituted with from 1 to5 substituents; R₂ is straight or branched alkyl of from 1 to 12 carbonatoms substituted or unsubstituted, cycloalkyl of from 3 to 12 carbonatoms substituted or unsubstituted, aryl unsubstituted or substitutedwith from 1 to 5 substituents, or heteroaryl unsubstituted orsubstituted with from 1 to 3 substituents; R₃ is straight or branchedalkyl of from 1 to 12 carbon atoms substituted or unsubstituted,cycloalkyl of from 3 to 12 carbon atoms substituted or unsubstituted,aryl which is unsubstituted or substituted with from 1 to 5substituents, or heteroaryl unsubstituted or substituted with from 1 to3 substituents; and at least one of R₁ or R₂ or R₃ is independentlysubstituted by a total of from 1 to 4 substituents which enhance aqueoussolubility, said substituents independently selected from the groupconsisting of: sulfonic acid or SO₃H groups and amino groups selectedfrom the group consisting of morpholinyl, pyrrolidinyl, and piperazinyl,with the proviso that when R₂ is alkyl and is substituted, thesubstituent is not oxygen at the α-position to the furanone ring.
 2. Acompound according to claim 1 wherein R₁ is phenyl substituted with from1 to 5 substituents, R₂ is straight or branched alkyl of from 1 to 9carbon atoms substituted with from 1 to 7 substituents, R₃ is arylsubstituted or unsubstituted; and at least one of Groups R₁ or R₂ or R₃is independently substituted by a total of from 1 to 4 substituentswhich enhance aqueous solubility, said substituents are independentlyselected from the group consisting of sulfonic acid or SO₃H groups andamino groups selected from the group consisting of morpholinyl,pyrrolidinyl, and piperazinyl, with the proviso when R₂ is alkyl and issubstituted, the substituent is not oxygen at the α-position to thefuranone ring.
 3. A compound according to claim 1 wherein R₁ is phenylsubstituted with from 1 to 5 substituents; R₂ is straight or branchedalkyl of from 1 to 7 carbons substituted with from 1 to 7 substituents;R₃ is aryl substituted or unsubstituted; and at least one of thesubstituents on R₁ and/or R₂ and/or R₃ have a substituent selected from:

 wherein R⁵ is hydrogen or lower alkyl,

—O—(CH₂)₁₋₆-SO₃H, —NH—(CH₂)₁₋₆-SO₃H,


4. A compound according to claim 1 wherein R₁ is piperonyl,3,5-dimethoxyphenyl, or 3-methoxy-4,5-methylenedioxyphenyl; R₂ is4-(3-dimethylaminopropoxy)benzyl, 3-(3-dimethylaminopropoxy)benzyl,5-(3-dimethylaminopropoxy)-3,4-dimethoxybenzyl,5-(2-morpholin-4-yl-ethoxy)-3,4-dimethoxybenzyl,5-(3-morpholin-4-yl-propoxy)-3,4-dimethoxybenzyl,5-(3-(4-methyl-piperazin-1-yl)propoxy)-3,4-dimethoxybenzyl,5-(2-(4-methyl-piperazin-1-yl)ethoxy)-3,4-dimethoxybenzyl,4-(2-(4-methyl-piperazin-1-yl)ethoxy)benzyl,3-(2-(4-methyl-piperazin-1-yl)cthoxy)benzyl,4-(3-(4-methyl-piperazin-1-yl)propoxy)benzyl,3-(3-(4-methyl-piperazin-1-yl)propoxy)benzyl,4-(2-morpholin-4-yl-ethoxy)benzyl, 3-(2-morpholin-4-yl-ethoxy)benzyl,4-(2-pyrrolidinyl-ethoxy)benzyl, 3-(2-pyrrolidinyl-ethoxy)benzyl,4-(3-pyrrolidinyl-propoxy)benzyl, 3-(3-pyrrolidinyl-propoxy)benzyl,5-(3-pyrrolidinyl-propoxy)-3,4-dimethoxybenzyl,5-(2-pyrrolidinyl-ethoxy)-3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl,benzyl; R₃ is 3,4-dimethoxyphenyl, 3-methyl-4-methoxyphenyl,2,4-dimethoxyphenyl, 4-methoxyphenyl, 4-(3-dimethylaminopropoxy)phenyl,or 4-(2-morpholin-4-ylethoxy)phenyl; R4 is hydroxy; and at least one R₁and/or R₂ and/or R₃ is independently substituted by a total of from 1 to4 substituents which enhance aqueous solubility, said substituents areindependently selected from the group consisting of sulfonic acid orSO₃H groups and amino groups selected from the group consisting ofmorpholinyl, pyrrolidinyl, and piperazinyl, with the proviso when R₂ isalkyl and is substituted, the substituent is not oxygen at theα-position to the furanone ring.
 5. A compound according to claim 1 andselected from2-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydr-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-N-(2-morpholin-4-yl-ethyl)-acetamide,3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one,3-Benzo[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-[3-(2-morpholin-4yl-ethoxy)-benzyl]-5H-furan-2-one,3-Benzo[1,3]dioxol-5-yl-5-hydroxy-4-[3-methoxy-4,5-bis-(2-morpholin-4-yl-ethoxy)-benzyl]-5-(4-methoxy-phenyl)-5H-furan-2-one,3-Benzo[1,3]dioxol-5-yl-4-[3,4-dimethoxy-5-(3-morpholin-4-yl-propoxy)-benzyl]-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,3-Benzo[1,3]dioxol-5-yl-4-{3,4-dimethyoxy-5-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one,3-{5-[4-Benzo[1,3]dioxol-5-yl-2-hydroxy-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-3-ylmethyl]-2,3-dimethoxy-phenoxy}-propane-1-sulfonicacid, 3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-[3-(3-morpholin-4-yl-propoxy)-benzyl]-5H-furan-2-one,3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-{3-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-5H-furan-2-one,and4-{3,4-Dimethoxy-5-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-3-(3,5-dimethoxy-phenyl)-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one.6. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 in admixture with apharmaceutically acceptable excipient, diluent, and/or carrier.
 7. Amethod of inhibiting elevated levels of endothelin comprisingadministering to a host suffering therefore a therapeutically effectiveamount of a composition according to claim 1 in unit dosing form.
 8. Amethod of treating vascular diseases selected from therosclerosis,restenosis, and Raynaud's phenomenon comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 9. A method of treating mildor severe congestive heart failure comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 10. A method of treatingcerebral ischemia, cerebral infarction, or embolic stroke, comprisingadministering to a host suffering therefrom a therapeutically effectiveamount of a compound according to claim 1 in unit dosage form.
 11. Amethod of treating cerebral vasospasm, subarachnoid hemorrhage orhemorrhagic stroke comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 12. A method of treating diabetescomprising administering to a host suffering therefrom a therapeuticallyeffective amount of a compound according to claim 1 in unit dosage form.13. A method of treating gastric ulceration and mucosal damage, ischemicbowel disease, or Chrohn's disease comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 14. A method of treatingessential and malignant hypertension comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 15. A method of treatingpulmonary hypertension or pulmonary hypertension after bypass surgerycomprising administering to a host suffering therefrom a therapeuticallyeffective amount of a compound according to claim 1 in unit dosage form.16. A method of treating cancer selected from meningiomas, malignanthemangioendothelioma and prostate cancer, comprising administering to ahost suffering therefrom a therapeutically effective amount of acompound according to claim 1 in unit dosage form.
 17. A method oftreating myocardial infarction or ischemia comprising administering to ahost suffering therefrom a therapeutically effective amount of acompound according to claim 1 in unit dosage form.
 18. A method oftreating acute or chronic renal failure, renal ischemia, orradiocontrast-induced nephrotoxicity comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 19. A method of treatingendotoxic, septic or hemorrhagic shock comprising administering to ahost suffering therefrom a therapeutically effective amount of acompound according to claim 1 in unit dosage form.
 20. A method oftreating angina comprising administering to a host suffering therefrom atherapeutically effective amount of a compound according to claim 1 inunit dosage form.
 21. A method of treating preeclampsia comprisingadministering to a host suffering therefrom a therapeutically effectiveamount of a compound according to claim 1 in unit dosage form.
 22. Amethod of treating asthma comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 23. A method of treating arrhythmiascomprising administering to a host suffering therefrom a therapeuticallyeffective amount of a compound according to claim 1 in unit dosage form.24. A method of treating benign prostatic hyperplasia comprisingadministering to a host suffering therefrom a therapeutically effectiveamount of a compound according to claim 1 in unit dosage form.
 25. Amethod of treating glaucoma comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 26. A method of treating male penileerectile dysfunction comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 27. A method of treating cryptogenicfibrosing alveolitis comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 28. A process for the preparation ofnonpetide endothelin antagonists with increased water solubility ofFormula I above comprising: 1) condensing an aldehyde of Formula

 with acetophenone-type compound, R₁—CHO, in basic solution to product achalcone derivative,

2) treating the product of Step 1) above with HCN in a solvent toproduce a nitrile,

3) hydrolyzing the nitrile of Step 2) above with an acidic solution toproduct the ester,

4) condensing the ester from Step 3) above with an aldehyde, R-CHO, insolvent using a base and cyclizing it with acid to produce a compound ofFormula I as in claim
 1. 29. A process for the preparation of nonpeptideendothelin antagonists with increased water solubility of Formula Iabove comprising: 1) treating a butenolide containing a leaving groupselected from halogen, mesylate, tosylate, or triflate at R₁, R₂, or R₃(R₂ is shown),

 with a primary amine, secondary amine, or sodium sulfite to produce acompound,

where Y is a morpholinyl group, a pyrrolidinyl group, a piperazinylgroup, or sulfonic acid (sodium salt).